Aminothiazole inhibitors of cyclin dependent kinases

ABSTRACT

Compounds of the formula ##STR1## and pharmaceuticaly acceptable salts thereof. As used in formula I, and throughout the specification, the symbols have the following meanings: 
     R 1  and R 2  are independently hydrogen, fluorine or alkyl; 
     R 3  is aryl or heteroaryl 
     R 4  is hydrogen, alkyl, cycloalkyl, aryl, cycloalkylalkyl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl; or 
     CO-alkyl, 
     CONH-alkyl, 
     COO-alkyl, 
     SO 2  -alkyl, 
     C(NCN)NH-alkyl, 
     C(NNO 2 )NH-alkyl, 
     C(NH)NH-alkyl, 
     C(NH)NHCO-alkyl, 
     C(NOR 6 )NH-alkyl, 
     R 5  is hydrogen or alkyl; 
     R 6  is hydrogen, alkyl, cycloalkyl, aryl, cycloalkylakyl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl or heterocycloalkylalkyl; 
     m is an integer of 0 to 2; and 
     n is an integer of 1 to 3. 
     The compounds of formula I are protein kinase inhibitors and are useful in the treatment and prevention of proliferative diseases, for example, cancer, inflammation and arthritis. They may also be useful in the treatment of neurodegenerative diseases such as Alzheimer&#39;s disease, cardiovascular diseases, viral diseases and fungal diseases.

This application claims benefit of Provisional Appl. No. 60/065,195filed Nov. 12, 1997.

BRIEF DESCRIPTION OF THE INVENTION

The present invention is directed to compounds of the formula ##STR2##and pharmaceutically acceptable salts thereof. As used in formula I, andthroughout the specification, the symbols have the following meanings:

R₁ and R₂ are independently hydrogen, fluorine or alkyl;

R₃ is aryl or heteroaryl

R₄ is hydrogen, alkyl, cycloalkyl, aryl, cycloalkylalkyl, arylalkyl,heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl; or

CO-alkyl, CO-cycloalkyl, CO-aryl, CO-alkyl-cycloalkyl, CO-alkyl-aryl,CO-heteroaryl, CO-alkyl-heteroaryl, CO-heterocycloalkyl,CO-alkyl-heterocycloalkyl; or

CONH-alkyl, CONH-cycloalkyl, CONH-aryl, CONH-alkyl-cycloalkyl,CONH-alkyl-aryl, CONH-heteroaryl, CONH-alkyl-heteroaryl,CONH-heterocycloalkyl, CONH-alkyl-heterocycloalkyl; or

COO-alkyl, COO-cycloalkyl, COO-aryl, COO-alkyl-cycloalkyl,COO-alkyl-aryl, COO-heteroaryl, COO-alkyl-heteroaryl,COO-heterocycloalkyl, COO-alkyl-heterocycloalkyl; or SO₂ -alkyl, SO₂-cycloalkyl, SO₂ -aryl, SO₂ -alkyl-cycloalkyl, SO₂ -alkyl-aryl, SO₂-heteroaryl, SO₂ -alkyl-heteroaryl, SO₂ -heterocycloalkyl, SO₂-alkyl-heterocycloalkyl; or

C(NCN)NH-alkyl, C(NCN)NH-cycloalkyl, C(NCN)NH-aryl,C(NCNNH)-alkyl-cycloalkyl, C(NCN)NH-alkyl-aryl, C(NCN)NH-heteroaryl,C(NCN)NH-alkyl-heteroaryl, C(NCN)NH-heterocycloalkyl,C(NCN)NH-alkyl-heterocylcoalkyl; or

C(NNO₂)NH-alkyl, C(NNO₂)NH-cycloalkyl, C(NNO₂)NH-aryl,C(NNO₂)NH-alkyl-cycloalkyl, C(NNO₂)NH-alkyl-aryl, C(NNO₂)NH-heteroaryl,C(NNO₂)NH-alkyl-heteroaryl, C(NNO₂)NH-heterocyloalkyl,C(NNO₂)NH-alkyl-heterocycloalkyl; or

C(NH)NH-alkyl, C(NH)NH-cycloalkyl, C(NH)NH-aryl,C(NH)NH-alkyl-cycloalkyl, C(NH)NH-alkyl-aryl, C(NH)NH-heteroaryl,C(NH)NH-alkyl-heteroaryl, C(NH)NH-heterocycloalkyl,C(NH)NH-alkyl-heterocycloalkyl; or

C(NH)NHCO-alkyl, C(NH)NHCO-cycloalkyl, C(NH)NHCO-aryl,C(NH)NHCO-alkyl-cycloalkyl, C(NH)NHCO-alkyl-aryl, C(NH)NHCO-heteroaryl,C(NH)NHCO-alkyl-heteroaryl, C(NH)NHCO-heterocylcloalkyl,C(NH)NHCO-alkyl-heterocycloalkyl; or

C(NOR₆)NH-alkyl, C(NOR₆)NH-cycloalkyl, C(NOR₆)NH-aryl,C(NOR₆)NH-alkyl-cycloalkyl, C(NOR₆)NH-alkyl-aryl, C(NOR₆)NH-heteroaryl,C(NOR₆)NH-alkyl-heteroaryl, C(NOR₆)NH-heterocylcoalkyl,C(NOR₆)NH-alkyl-heterocycloalkyl;

R₅ is hydrogen or alkyl;

R₆ is hydrogen, alkyl, cycloalkyl, aryl, cycloalkylakyl, arylalkyl,heteroaryl, heteroarylalkyl, heterocycloalkyl or heterocycloalkylalkyl;

m is an integer of 0 to 2; and

n is an integer of 1 to 3.

The compounds of formula I are protein kinase inhibitors and are usefulin the treatment and prevention of proliferative diseases, for example,cancer, inflammation and arthritis. They may also be useful in thetreatment of neurodegenerative diseases such as Alzheimer's disease,cardiovascular diseases, viral diseases and fungal diseases.

DESCRIPTION OF THE INVENTION

The present invention provides for compounds of formula I,pharmaceutical compositions employing such compounds and for methods ofusing such compounds.

Listed below are definitions of various terms used to describe thecompounds of the instant invention. These definitions apply to the termsas they are used throughout the specification (unless they are otherwiselimited in specific instances) either individually or as part of alarger group.

It should be noted that any heteroatom with unsatisfied valances isassumed to have the hydrogen atom to satisfy the valances.

Carboxylate anion refers to a negatively charged group --COO⁻⁻.

The term "alkyl" or "alk" refers to a monovalent alkane (hydrocarbon)derived radical containing from 1 to 12 carbon atoms unless otherwisedefined. An alkyl group is an optionally substituted straight, branchedor cyclic saturated hydrocarbon group. When substituted, alkyl groupsmay be substituted with up to four substituent groups, R as defined, atany available point of attachment. When the alkyl group is said to besubstituted with an alkyl group, this is used interchangeably with"branched alkyl group". Exemplary unsubstituted such groups includemethyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, isobutyl, pentyl,hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl,2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl, and the like.Exemplary substituents may include but are not limited to one or more ofthe following groups: halo (such as F, Cl, Br, I), haloalkyl (such asCCl₃ or CF₃), alkoxy, alkylthio, hydroxy, carboxy (--COOH),alkyloxycarbonyl (--C(O)R), alkylcarbonyloxy (--OCOR), amino (--NH₂),carbamoyl (--NHCOOR-- or --OCONHR--), urea (--NHCONHR--) or thiol(--SH). Alkyl groups as defined may also comprise one or more carbon tocarbon double bonds or one or more carbon to carbon triple bonds.

The term "alkenyl" refers to a hydrocarbon radical straight, branched orcyclic containing from 2 to 12 carbon atoms and at least one carbon tocarbon double bond.

The term "alkynyl" refers to a hydrocarbon radical straight, branched orcyclic containing from 2 to 12 carbon atoms and at least one carbon tocarbon triple bond.

Cycloalkyl is a specie of alkyl containing from 3 to 15 carbon atoms,without alternating or resonating double bonds between carbon atoms. Itmay contain from 1 to 4 rings. Exemplary unsubstituted such groupsinclude cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl,etc. Exemplary substituents include one or more of the following groups:halogen, alkyl, alkoxy, alkyl hydroxy, amino, nitro, cyano, thiol and/oralkylthio.

The terms "alkoxy" or "alkylthio", as used herein, denote an alkyl groupas described above bonded through an oxygen linkage (--O--) or a sulfurlinkage (--S--), respectively.

The term "alkyloxycarbonyl", as used herein, denotes an alkoxy groupbonded through a carbonyl group. An alkoxycarbonyl radical isrepresented by the formula: --C(O)OR, where the R group is a straight orbranched C₁₋₆ alkyl group.

The term "alkylcarbonyl" refers to an alkyl group bonded through acarbonyl group.

The term "alkylcarbonyloxy", as used herein, denotes an alkylcarbonylgroup which is bonded through an oxygen linkage.

The term "arylalkyl", as used herein, denotes an aromatic ring bonded toan alkyl group as described above.

The term "aryl" refers to monocyclic or bicyclic aromatic rings, e.g.phenyl, substituted phenyl and the like, as well as groups which arefused, e.g., napthyl, phenanthrenyl and the like. An aryl group thuscontains at least one ring having at least 6 atoms, with up to five suchrings being present, containing up to 22 atoms therein, with alternating(resonating) double bonds between adjacent carbon atoms or suitableheteroatoms. Aryl groups may optionally be substituted with one or moregroups including, but not limited to halogen, alkyl, alkoxy, hydroxy,carboxy, carbamoyl, alkyloxycarbonyl, nitro, trifluoromethyl, amino,cycloalkyl, cyano, alkyl S(O)_(m) (m=O, 1, 2), or thiol.

The term "heteroaryl" refers to a monocyclic aromatic hydrocarbon grouphaving 5 or 6 ring atoms, or a bicyclic aromatic group having 8 to 10atoms, containing at least one heteroatom, O, S, or N, in which a carbonor nitrogen atom is the point of attachment, and in which one or twoadditional carbon atoms is optionally replaced by a heteroatom selectedfrom O or S, and in which from 1 to 3 additional carbon atoms areoptionally replaced by nitrogen heteroatoms, said heteroaryl group beingoptionally substituted as described herein. Exemplary heteroaryl groupsinclude the following: thienyl, furyl, pyrrolyl, pyridinyl, imidazolyl,pyrrolidinyl, piperidinyl, thiazolyl, oxazolyl, triazolyl, pyrazolyl,isoxazolyl, isothiazolyl, pyrazinyl, pyridazinyl, pyrimidinal,triazinylazepinyl, indolyl, isoindolyl, quinolinyl, isoquinolinyl,benzothiazolyl, benzoxazolyl, benzimidazolyl, benzoxadiazolyl,benzofurazanyl and tetrahydropyranyl. Exemplary substituents include oneor more of the following: halogen, alkyl, alkoxy, hydroxy, carboxy,carbamoyl, alkyloxycarbonyl, trifluoromethyl, cycloalkyl, nitro, cyano,amino, alkylS(O)_(m) (m=0, 1, 2), or thiol.

The term "heteroarylium" refers to heteroaryl groups bearing aquaternary nitrogen atom and thus a positive charge.

The term "heterocycloalkyl" refers to a cycloalkyl group (nonaromatic)in which one of the carbon atoms in the ring is replaced by a heteroatomselected from O, S or N, and in which up to three additional carbonatoms may be replaced by said heteroatoms.

The term "quaternary nitrogen" refers to a tetravalent positivelycharged nitrogen atom including, e.g. the positively charged nitrogen ina tetraalkylammonium group (e.g. tetramethylammonium,N-methylpyridinium), the positively charged nitrogen in protonatedammonium species (e.g. trimethylhydroammonium, N-hydropyridinium), thepositively charged nitrogen in amine N-oxides (e.g.N-methyl-morpholine-N-oxide, pyridine -N-oxide), and the positivelycharged nitrogen in an N-amino-ammonium group (e.g. N-aminopyridinium).

The term "heteroatom" means O, S or N, selected on an independent basis.

The term "halogen" or "halo" refers to chlorine, bromine, fluorine oriodine.

When a functional group is termed "protected", this means that the groupis in modified form to preclude undesired side reactions at theprotected site. Suitable protecting groups for the compounds of thepresent invention will be recognized from the present application takinginto account the level of skill in the art, and with reference tostandard textbooks, such as Greene, T. W. et al., Protective Groups inOrganic Synthesis, Wiley, N.Y. (1991).

Suitable examples of salts of the compounds according to the inventionwith inorganic or organic acids are hydrochloride, hydrobromide,sulfate, phosphate. Salts which are unsuitable for pharmaceutical usesbut which can be employed, for example, for the isolation orpurification of free compounds I or their pharmaceutically acceptablesalts, are also included.

All stereoisomers of the compounds of the instant invention arecontemplated, either in admixture or in pure or substantially pure form.The definition of the compounds according to the invention embraces allpossible stereoisomers and their mixtures. It very particularly embracesthe racemic forms and the isolated optical isomers having the specifiedactivity. The racemic forms can be resolved by physical methods, suchas, for example, fractional crystallization, separation orcrystallization of diastereomeric derivatives or separation by chiralcolumn chromatography. The individual optical isomers can be obtainedfrom the racemates by conventional methods, such as, for example, saltformation with an optically active acid followed by crystallization.

It should be understood that solvates (e.g., hydrates) of the compoundsof formula I are also within the scope of the present invention. Methodsof solvation are generally known in the art. Accordingly, the compoundsof the instant invention may be in the free or hydrate form, and may beobtained by methods exemplified by the following schemes. ##STR3##

As illustrated in Scheme 1, compounds of formula I where X is S areprepared by reacting 2-aminothiazole (II) with bromine in the presenceof sodium or potassium thiocyanate to obtain a thiocyanatedaminothiazole, specifically 5-thiocyanatoaminothiazole (III). CompoundIII is then reacted with R₄ -L, where L is a leaving group such as ahalogen, in the presence of a base such as triethylamine to provide a5-thiocyanatothiazole intermediate (IV), where R₄ is as defined in thespecification. The intermediate (IV) is then reduced to a thiol (V)using reducing agents such as dithiothreitol (DTT), sodium borohydride,zinc or other known reducing agents. Compound (V) is then reacted withalkyl, aryl or heteroaryl halides, such as R₃ (CR₁ R₂)_(n) -L, where Lis a leaving group such as a halogen, in the presence of a base such aspotassium carbonate to obtain compounds of formula I. The steps ofreducing the thiocyanothiazole intermediate (IV) to the thiol (V), andthe reaction of the reduced thiol (V) to provide compounds of formula Iwhere X is S, may be carried out sequentially without purification.##STR4##

In Scheme 2, 5-thioacetyl-2-acetylaminothiazole of structure VI isreacted with an alkoxide such as potassium t-butoxide in alcohol or THFsolvent and the resulting thiol is reacted in situ with a group offormula R₃ (CR₁ R₂)_(n) -L (where L is a leaving group, such as ahalogen) such as 2-halomethyloxazole (VII) to provide a compound such asformula VIII, wherein R₁ and R₂ are hydrogen, and R₆ is acetyl. The2-halomethyloxazole compounds of formula VII may be prepared usingseveral synthetic routes known in the art. Chem. Pharm. Bull. 30, 1865(1982); Bull. Chem. Soc. Japan (52, 3597 (1979); JCS Chem. Comm. 322(1981); Comprehensive Heterocyclic Chemistry, vol. 6, 177, edited by A.Katritzky and C. W. Rees, Pergamon Press (1984).

Compounds of formula VIII (a compound of formula I where R₄ is acetyland X is sulfur) can be hydrolyzed in the presence of a base such assodium hydroxide to provide a compound of formula IX. A compound offormula IX may then be reacted with R₄ -L, in the presence of a basesuch as triethylamine, where L is a leaving group such as a halogen, togive compounds of formula I where X is sulfur. In this manner, compoundsof formula IX, which is a compound of formula I where R₄ is hydrogen,can be treated with agents such as isothiocyanates, halides, acylhalides, chloroformates, isocyanates or sulfonyl chlorides to providethioureas, amines, amides, carbamates, ureas or sulfonamides. Theprocedures in Scheme 2 specifically illustrate a methyloxazole group,but are general for all R₃ (CR₁ R₂)_(n) - groups specified by formula I.

Alternatively, compounds of formula VII, where L is bromine, may beprepared by halogenation of 2-methyloxazole using N-bromosuccinimide inthe presence of dibenzoylperoxide. ##STR5##

Scheme 3 lustrates an alternative method of preparing compound VII,which is a compound of formula R₃ (CR₁ R₂)_(n) -L where L is chlorineand n is the integer 1. In this scheme, compound VII is prepared by thereaction of a compound of formula X and formula XI in the presence of abase such as triethylamine to provide compounds of formula XII. CompoundXII may be oxidized by an oxidant such as oxalylchloride/DMSO in thepresence of a base such as triethylamine to provide a compound offormula XIII which may be cyclized by an agent such as phosphorousoxychloride to provide compounds of formula VII, wherein L is chlorine.Alternatively, compounds of formula XIII may be prepared by reaction ofthe amino ketone correponding to X with an acid chloride such as XI.##STR6##

Compounds of formula VII, where L is chlorine, may also be prepared fromthe reaction of diazoketones as illustrated by formula XIV in Scheme 4with chloronitriles, such as indicated by formula XV, in the presence ofBF₃ etherate to provide compounds of formula VII, wherein L is chlorine.##STR7##

In Scheme 5, starting compound XVI denotes a resin-bound benzyl alcoholsupport used for solid phase synthesis which is prepared from aMerrifield resin denoted as , and 2-methoxy-4-hydroxybenzaldehyde,followed by reduction with reducing agents such as NaBH₄. In step 1,starting compound XVI is treated with triphosgene and triphenylphosphine(PPh₃) in dichloromethane to give the chlorobenzyl resin of formulaXVII. In step 2, a thiocyanato trifluoroacetamide (XVIII) is alkylatedwith the resin-bound benzyl chloride (XVII) in the presence ofdiisopropylethylamine (DIPEA) to form a resin-bound thiocyanate (XIX).The thiocyanato trifluoroacetamide compound of formula XVII is preparedby reacting 5-thiocyanatoaminothiazole of formula III (Scheme I) withtrifluoroacetic anhydride using a base such as 2,6-lutidine.

The resin-bound thiocyanate (XIX) is then reduced to a resin-bound thiol(XX) in step 3 with reducing agent such as dithiothreitol (DTT) intetrahydrofuran (THF) and methanol. The resulting resin-bound thiol (XX)is reacted with R₃ (CR₁ R₂)_(n) -L, where L is a leaving group, in thepresence of a base such as 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU) at80° C. in dimethylformamide (DMF) to form compounds of formula XXI (step4). Deprotection of the trifluoroacetyl group of compound XXI isperformed in step 5 using sodium borohydride to provide a compound offormula XXII. In step 6, the deprotected compound XXII is reacted withR₆ X, where X is a leaving group, in the presence of a base such asdiisopropylethylamine to provide compounds of formula XXIII. The productis then cleaved from the solid phase resin in step 7 withtrifluoroacetic acid (TFA) to give compounds of formula I where X issulfur. Compounds of formula I where X is S(O)_(m) and m is 1 or 2 maybe prepared from compounds of formula I where m is 0 by oxidation withan oxidant such as sodium periodate, meta-chloroperbenzoic acid, oroxone.

The starting compounds of Schemes 1-5 are commercially available or maybe prepared by methods known to one of ordinary skill in the art.

All compounds of formula I may be prepared by modification of theprocedures described herein.

The preferred compounds of formula I are those where:

R₁ and R₂ are independently hydrogen, fluorine or alkyl; ##STR8##wherein Y is oxygen, sulfure or NR₉ ;

R₄ is hydrogen, alkyl, cycloalkyl, aryl, cycloalkylalkyl, arylalkyl,heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl; or

CO-alkyl, CO-cycloalkyl, CO-aryl, CO-alkyl-cycloalkyl, CO-alkyl-aryl,CO-heteroaryl, CO-alkyl-heteroaryl, CO-heterocycloalkyl,CO-alkyl-heterocycloalkyl; or

CONH-alkyl, CONH-cycloalkyl, CONH-aryl, CONH-alkyl-cycloalkyl,CONH-alkyl-aryl, CONH-heteroaryl, CONH-alkyl-heteroaryl,CONH-heterocycloalkyl, CONH-alkyl-heterocycloalkyl; or

COO-alkyl, COO-cycloalkyl, COO-aryl, COO-alkyl-cycloalkyl,COO-alkyl-aryl, COO-heteroaryl, COO-alkyl-heteroaryl,COO-heterocycloalkyl, COO-alkyl-heterocycloalkyl; or

SO₂ -alkyl, SO₂ -cycloalkyl, SO₂ -aryl, SO₂ -alkyl-cycloalkyl, SO₂-alkyl-aryl, SO₂ -heteroaryl, SO₂ -alkyl-heteroaryl, SO₂-heterocycloalkyl, SO₂ -alkyl-heterocycloalkyl; or

C(NCN)NH-alkyl, C(NCN)NH-cycloalkyl, C(NCN)NH-aryl,C(NCNNH)-alkyl-cycloalkyl, C(NCN)NH-alkyl-aryl, C(NCN)NH-heteroaryl,C(NCN)NH-alkyl-heteroaryl, C(NCN)NH-heterocycloalkyl,C(NCN)NH-alkyl-heterocylcoalkyl; or

C(NNO₂)NH-alkyl, C(NNO₂)NH-cycloalkyl, C(NNO₂)NH-aryl,C(NNO₂)NH-alkyl-cycloalkyl, C(NNO₂)NH-alkyl-aryl, C(NNO₂)NH-heteroaryl,C(NNO₂)NH-alkyl-heteroaryl, C(NNO₂)NH-heterocyloalkyl,C(NNO₂)NH-alkyl-heterocycloalkyl; or

C(NH)NH-alkyl, C(NH)NH-cycloalkyl, C(NH)NH-aryl, C(NH)NH-alkyl-cycloalkyl, C(NH)NH-alkyl-aryl, C(NH)NH-heteroaryl,C(NH)NH-alkyl-heteroaryl, C(NH)NH-heterocycloalkyl,C(NH)NH-alkyl-heterocycloalkyl; or

C(NH)NHCO-alkyl, C(NH)NHCO-cycloalkyl, C(NH)NHCO-aryl,C(NH)NHCO-alkyl-cycloalkyl, C(NH)NHCO-alkyl-aryl, C(NH)NHCO-heteroaryl,C(NH)NHCO-alkyl-heteroaryl, C(NH)NHCO-heterocylcloalkyl,C(NH)NHCO-alkyl-heterocycloalkyl; or

C(NOR₆)NH-alkyl, C(NOR₆)NH-cycloalkyl, C(NOR₆)NH-aryl,C(NOR₆)NH-alkyl-cycloalkyl, C(NOR₆)NH-alkyl-aryl, C(NOR₆)NH-heteroaryl,C(NOR₆)NH-alkyl-heteroaryl, C(NOR₆)NH-heterocylcoalkyl,C(NOR₆)NH-alkyl-heterocycloalkyl;

R₅ is hydrogen; and

R₆ is hydrogen, alkyl, cycloalkyl, aryl, cycloalkylakyl, arylalkyl,heteroaryl, heteroarylalkyl, heterocycloalkyl or heterocycloalkylalkyl;

R₇ and R₈ are independently hydrogen, alkyl, cycloalkyl, aryl,alkylcycloalkyl, alkylaryl, heteroaryl, alkylheteroaryl,heterocycloalkyl, alkylheterocycloalkyl or halogen;

R₉ is H or alkyl;

m is the integer 0; and

n is the integer 1.

The most preferred compounds of formula I are those where:

R₁ is hydrogen;

R₂ is hydrogen, fluorine or alkyl;

R₃ is a substituted oxazole having the configuration: ##STR9##

R₄ is CO-alkyl, CO-alkyl-aryl, CO-cycloalkyl, CO-alkyl-heteroaryl,CO-alkyl-heteroalkyl, CO-alkyl-heterocycloalkyl, CONH-alkyl,CONH-alkyl-aryl, CONH-cycloalkyl, or CONH-alkyl-heterocycloalkyl;

R₅ is hydrogen;

R₇ is hydrogen;

R₈ is an alkyl group, such as tert-butyl;

m is the integer 0; and

n is the integer 1.

The compounds according to the invention have pharmacologicalproperties; in particular, the compounds of formula I are inhibitors ofprotein kinases such as the cyclin dependent kinases (cdks), forexample, cdc2 (cdk1), cdk2, and cdk4. The novel compounds of formula Iare expected to be useful in the therapy of proliferative diseases suchas cancer, autoimmune diseases, viral diseases, fungal diseases,neurodegenerative disorders and cardiovascular disease.

More specifically, the compounds of formula I are useful in thetreatment of a variety of cancers, including (but not limited to) thefollowing:

carcinoma, including that of the bladder, breast, colon, kidney, liver,lung, including small cell lung cancer, esophagus, gall bladder, ovary,pancreas, stomach, cervix, thyroid, prostate, and skin, includingsquamous cell carcinoma;

hematopoietic tumors of lymphoid lineage, including leukemia, acutelymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma,T-cell lymphoma, Hodgkins lymphoma, non-Hodgkins lymphoma, hairy celllymphoma and Burkett's lymphoma;

hematopoietic tumors of myeloid lineage, including acute and chronicmyelogenous leukemias, myelodysplastic syndrome and promyelocyticleukemia;

tumors of mesenchymal origin, including fibrosarcoma andrhabdomyosarcoma;

tumors of the central and peripheral nervous system, includingastrocytoma, neuroblastoma, glioma and schwannomas; and

other tumors, including melanoma, seminoma, teratocarcinoma,osteosarcoma, xenoderoma pigmentosum, keratoctanthoma, thyroidfollicular cancer and Kaposi's sarcoma.

Due to the key role of cdks in the regulation of cellular proliferationin general, inhibitors could act as reversible cytostatic agents whichmay be useful in the treatment of any disease process which featuresabnormal cellular proliferation, e.g., benign prostate hyperplasia,familial adenomatosis polyposis, neuro-fibromatosis, atherosclerosis,pulmonary fibrosis, arthritis, psoriasis, glomerulonephritis, restenosisfollowing angioplasty or vascular surgery, hypertrophic scar formation,inflammatory bowel disease, transplantation rejection, endotoxic shock,and fungal infections.

Compounds of formula I may also be useful in the treatment ofAlzheimer's disease, as suggested by the recent finding that cdk5 isinvolved in the phosphorylation of tau protein (J. Biochem, 117, 741-749(1995)).

Compounds of formula I may induce or inhibit apoptosis. The apoptoticresponse is aberrant in a variety of human diseases. Compounds offormula I, as modulators of apoptosis, will be useful in the treatmentof cancer (including but not limited to those types mentionedhereinabove), viral infections (including but not limited to herpevirus,poxvirus, Epstein-Barr virus, Sindbis virus and adenovirus), preventionof AIDS development in HIV-infected individuals, autoimmune diseases(including but not limited to systemic lupus, erythematosus, autoimmunemediated glomerulonephritis, rheumatoid arthritis, psoriasis,inflammatory bowel disease, and autoimmune diabetes mellitus),neurodegenerative disorders (including but not limited to Alzheimer'sdisease, AIDS-related dementia, Parkinson's disease, amyotrophic lateralsclerosis, retinitis pigmentosa, spinal muscular atrophy and cerebellardegeneration), myelodysplastic syndromes, aplastic anemia, ischemicinjury associated with myocardial infarctions, stroke and reperfusioninjury, arrhythmia, atherosclerosis, toxin-induced or alcohol relatedliver diseases, hematological diseases (including but not limited tochronic anemia and aplastic anemia), degenerative diseases of themusculoskeletal system (including but not limited to osteoporosis andarthritis) aspirin-sensitive rhinosinusitis, cystic fibrosis, multiplesclerosis, kidney diseases and cancer pain.

Compounds of formula I, as inhibitors of the cdks, can modulate thelevel of cellular RNA and DNA synthesis. These agents would therefore beuseful in the treatment of viral infections (including but not limitedto HIV, human papilloma virus, herpesvirus, poxvirus, Epstein- Barrvirus, Sindbis virus and adenovirus).

Compounds of formula I may also be useful in the chemoprevention ofcancer. Chemoprevention is defined as inhibiting the development ofinvasive cancer by either blocking the initiating mutagenic event or byblocking the progression of pre-malignant cells that have alreadysuffered an insult or inhibiting tumor relapse.

Compounds of formula I may also be useful in inhibiting tumorangiogenesis and metastasis.

Compounds of formula I may also act as inhibitors of other proteinkinases, e.g., protein kinase C, her2, raf1, MEK1, MAP kinase, EGFreceptor, PDGF receptor, IGF receptor, PI3 kinase, weel kinase, Src, Abland thus be effective in the treatment of diseases associated with otherprotein kinases.

The compounds of this invention may also be useful in combination(administered together or sequentially) with known anti-cancertreatments such as radiation therapy or with cytostatic or cytotoxicagents, such as for example, but not limited to, DNA interactive agents,such as cisplatin or doxorubicin; topoisomerase II inhibitors, such asetoposide; topoisomerase I inhibitors such as CPT-11 or topotecan;tubulin interacting agents, such as paclitaxel, docetaxel or theepothilones; hormonal agents, such as tamoxifen; thymidilate synthaseinhibitors, such as 5-fluorouracil; and anti-metabolites, such asmethoxtrexate.

If formulated as a fixed dose, such combination products employ thecompounds of this invention within the dosage range described below andthe other pharmaceutically active agent or treatment within its approveddosage range. For example, the cdc2 inhibitor olomucine has been foundto act synergistically with known cytotoxic agents in inducing apoptosis(J. Cell Sci., 108, 2897 (1995)). Compounds of formula I may also beadministered sequentially with known anticancer or cytotoxic agents whena combination formulation is inappropriate. The invention is not limitedin the sequence of administration; compounds of formula I may beadministered either prior to or after administration of the knownanticancer or cytotoxic agent. For example, the cytotoxic activity ofthe cyclin-dependent kinase inhibitor flavopiridol is affected by thesequence of administration with anticancer agents. Cancer Research, 57,3375 (1997).

The pharmacological properties of the compounds of this invention may beconfirmed by a number of pharmacological assays. The exemplifiedpharmacological assays which follow have been carried out with thecompounds according to the invention and their salts. The compounds ofexamples 1 to 8 exhibited cdc2/cyclin B1 kinase activity with IC₅₀values less than 50 μM. The compounds of examples 1 to 8 exhibitedcdk2/cyclin E kinase activity with IC₅₀ values less than 50 μM. Thecompounds of examples 1 to 8 exhibited cdk4/cyclin D1 kinase activitywith IC₅₀ values less than 50 μM.

cdc2/cvclin B1 Kinase Assay

cdc2/cyclin B1 kinase activity was determined by monitoring theincorporation of ³² P into histone H1. The reaction consisted of 50 ngbaculovirus expressed GST-cdc2, 75 ng baculovirus expressed GST-cyclinB1, 1 μg histone HI (Boehringer Mannheim), 0.2 mCi of ³² P g-ATP and 25mM ATP in kinase buffer (50 mM Tris, pH 8.0, 10 mM MgCl₂, 1 mM EGTA, 0.5mM DTT). The reaction was incubated at 30° C. for 30 minutes and thenstopped by the addition of cold trichloroacetic acid (TCA) to a finalconcentration of 15% and incubated on ice for 20 minutes. The reactionwas harvested onto GF/C unifilter plates (Packard) using a PackardFiltermate Universal harvester, and the filters were counted on aPackard TopCount 96-well liquid scintillation counter (Marshak, D. R.,Vanderberg, M. T., Bae, Y. S., Yu, I. J., J. of Cellular Biochemistry,45, 391-400 (1991), incorporated by reference herein).

cdk2 cyclin E Kinase Assay

cdk2/cyclin E kinase activity was determined by monitoring theincorporation of ³² p into the retinoblastoma protein. The reactionconsisted of 2.5 ng baculovirus expressed GST-cdk2/cyclin E, 500 ngbacterially produced GST-retinoblastoma protein (aa 776-928), 0.2 mCi ³²p g-ATP and 25 mM ATP in kinase buffer (50 mM Hepes, pH 8.0, 10 mMMgCl₂, 5 mM EGTA, 2 mM DTT). The reaction was incubated at 30° C. for 30minutes and then stopped by the addition of cold trichloroacetic acid(TCA) to a final concentration of 15% and incubated on ice for 20minutes. The reaction was harvested onto GF/C unifilter plates (Packard)using a Packard Filtermate Universal harvester, and the filters werecounted on a Packard TopCount 96-well liquid scintillation counter.

cdk 4/cyclin D1 Kinase Activity

cdk4/cyclin D1 kinase activity was determined by monitoring theincorporation of ³² P in to the retinoblastoma protein. The reactionconsisted of 165 ng baculovirus expressed as GST-cdk4, 282 ngbacterially expressed as S-tag cyclin D1, 500 ng bacterially producedGST-retinoblastoma protein (aa 776-928), 0.2 μCi ³² P γ-ATP and 25 M ATPin kinase buffer (50 mM Hepes, pH 8.0, 10 mM MgCl₂, 5 mM EGTA, 2 mMDTT). The reaction was incubated at 30° C. for 1 hour and then stoppedby the addition of cold trichloroacetic acid (TCA) to a finalconcentration of 15% and incubated on ice for 20 minutes. The reactionwas harvested onto GF/C unifilter plates (Packard) using a PackardFiltermate Universal harvester, and the filters were counted on aPackard TopCount 96-well liquid scintillation counter (Coleman, K. G.,Wautlet, B. S., Morissey, D, Mulheron, J. G., Sedman, S., Brinkley, P.,Price, S., Wedster, K. R. (1997). Identification of CDK4 Sequencesinvolved in cyclin D, and p16 binding. J. Biol. Chem.272,30:18869-18874, incorporated by reference herein).

Further subject matter of the invention also includes pharmaceuticalsfor use as described above including controlling cancer, inflammationand arthritis, which contain at least one compound of the formula I asdefined above or at least one of its pharmacologically acceptable acidaddition salts, and the use of a compound of the formula I as definedabove for the preparation of a pharmaceutical having activity againstproliferative diseases as described previously including against cancer,inflammation and/or arthritis.

The following examples and preparations describe the manner and processof making and using the invention and are illustrative rather thanlimiting. It should be understood that there may be other embodimentswhich fall within the spirit and scope of the invention as defined bythe claims appended hereto. ##STR10##

A. Preparation of 1-benzyloxycarbonylamino-2-butanol

A mixture of 1-amino-2-butanol (5.5 g, 61.8 mmol), benzyl chloroformate(11.5 g, 67.6 mmol) and sodium carbonate (7.16 g, 67.7 mmol) in water(50 mL) was stirred at 0° C. for 3 h. Water (50 mL) was added to thereaction mixture and the product was extracted with methylene chloride(3×20 mL). The methylene chloride extract was dried over Na₂ SO₄ andconcentrated. The residue was passed through a short column (SiO₂,hexanes: ethyl acetate/10:1; then ethyl acetate) to afford1-benzyloxycarbonylamino-2-butanol (13.9 g, 100%) as a liquid.

¹ H NMR (CDCl₃) δ7.30 (m, 5 H), 5.45 (s, 1 H), 5.06 (s, 2 H), 3.57 (s, 1H), 3.31 (m, 1 H), 3.04 (m, 1 H), 2.91 (m, 1 H), 1.43 (m, 2 H), 0.91 (t,J=7.6 Hz, 3 H).

B. Preparation of 1-benzyloxycarbonylamino2-butanone

To methylene chloride (60 mL) at -78° C. under argon was added oxalylchloride (37 mL of 2 M solution in methylene chloride, 74 mmol),followed by DMSO (7.8 g, 100 mmol). The mixture was stirred at 78° C.for 20 min. and to this mixture was added a solution of1-benzyloxycarbonylamino-2-butanol (13.9 g, 61.8 mmol) in methylenechloride (40 mL). The mixture was stirred at -78° C. for 1 h andtriethylamine (21 mL) was added to the mixture. It was warmed to roomtemperature (rt) and washed successively with 1 N hydrochloric acid andaqueous sodium bicarbonate solution. The methylene chloride solution wasdried over MgSO₄ and concentrated to afford1-benzyloxycarbonylamino-2-butanone (11.2 g, 82%) as a solid, which wasenough pure for the next reaction. ¹ H NMR (CDCl₃) δ7.32 (m, 5 H), 5.50(s, 1 H), 5.06 (s, 2 H), 4.07 (s, 2 H), 2.43 (q, J=7.6 Hz, 2 H), 1.06(t, J=7.6 Hz, 3 H).

C. Preparation of 1-amino-2-butanone

A solution of 1-benzyloxycarbonylamino-2-butanone (9.30 mg, 42 mmol) inethanol (50 mL) and 1 N hydrochloric acid (46 mL) was stirred underhydrogen atmosphere in the presence of Pd/C (1.5 g, 10%) at rt for 4 h.The mixture was filtered through a celite bed and the filtrate solutionwas concentrated. The residue was triturated with ethyl ether to afford1-amino-2-butanone (5.3 g, 102%) as a hydrochloride salt. ¹ H NMR (CD₃OD) δ3.97 (s, 2 H), 2.60 (q, J=7.6 Hz, 2 H), 1.08 (t, J=7.6 Hz, 3 H).

D. Preparation of 2-amino-5-thiocyanatothiazole

2-Aminothiazole (41 g, 410 mM) and sodium thiocyanate (60 g, 740 mM,dried in a vacuum oven at 130° C. overnight) was dissolved in 450 mL ofanhydrous methanol and the solution was cooled in a cold water bath.Here was added bromine (23 mL, 445 mM) dropwise with good stirring.After the addition it was stirred for 4 h at rt. To the mixture 500 mLof water was added and it was stirred for 5 minutes, filtered through acelite bed and washed the bed with water. The pH of the filtratesolution was about 1. Most of the methanol was removed under the reducedpressure and pH of the solution was adjusted to about 7 by adding aq.sodium carbonate slowly with stirring. The precipitated solid wasfiltered and washed with water to obtain 37 g (57%) of the dark browncolored desired product after drying, mp 140-143° C. ¹ H NMR (CD₃ OD)δ7.33 (s, 1 H); MS (CI/NH₃) m/e 179 (M+Na)⁺, 158 (M+H)⁺.

E. Preparation of of 2-acetylamino-5-thiocyanatothiazole

To a mixture of 2-amino-5-thiocyanatothiazole (15.7 g, 0.1 mol) andpyridine (12 g, 0.15 mol) in methylene chloride (100 mL) was addedacetic anhydride (1.2 g, 0.12 mol) at rt. The mixture was stirred at rtfor 6 h. The mixture was concentrated to dryness and to the residue MeOH(50 mL) was added. The precipitates were collected and washed withwater. The solid was dried and recrystallized from MeOH to afford2-acetylamino-5-thiocyanatothiazole (15.2 g, 76%) as a solid, mp 212° C.¹ H NMR (CD₃ OD) δ7.79 (s, 1 H), 2.23 (s, 3 H).

F. Preparation of [[2-(acetylamino)-5-thiazolyl]thio]acetic acid1,1-dimethylethyl ester

To a mixture of 2-acetamino-5-thiocyanatothiazole (5.97 g, 30 mmol) inMeOH (360 mL) under argon was added dithiothreitol (9.26 g, 60 mmol) atrt. The mixture was stirred at rt for 2 h and it was concentrated toafford a reduced solid product. This solid product was dissolved in DMF(30 mL) and to this solution were added tert-butyl bromoacetate (5.85 g,30 mmol) and potassium carbonate (5.0 g, 36 mmol). The mixture wasstirred at rt for 2 h and water (200 mL) was added to the mixture. Theprecipitates were collected, washed with water and dried. The solid wasdissolved in methylene chloride (100 mL) and MeOH (10 mL) and filteredthrough a silica gel pad. The filtrate solution was concentrated toafford the desired product (7.5 g, 87%) as a solid, mp 162-163° C. ¹ HNMR (CDCl₃) δ12.2 (s, 1 H), 7.48 (s, 1 H), 3.37 (s, 2 H), 2.32 (s, 3 H),1.45 (s, 9 H); MS m/e 289 (M+H)⁺, 287 (M-H)⁻. HPLC (Column: YMC S3 ODS4.6×150 mm; flow rate: 2.5 mL/min; solvent system: 0-100% B in 8 min.Solvent A: 10% MeOH-90% water-0.2% H₃ PO₄ ; Solvent B: 90% MeOH-10%Water-0.2% H₃ PO₄ ; UV: 220 nm): retention time 6.44 min.

G. Preparation of [[2-(acetylamino)-5-thiazolyl]thio]acetic acid

A solution of [[2-(acetylamino)-5-thiazolyl]thio]acetic acid1,1-dimethylethyl ester (4.32 g, 15 mmol) in methylene chloride (30 mL)and trifluoroacetic acid (20 mL) was stirred at rt overnight andconcentrated in vacuo. To the residue was added ethyl ether (50 mL). Theprecipitated solid was collected, washed with ethyl ether and dried toafford the desired product (3.38 g, 97%) as a solid, mp 210° C. ¹ H NMR(CD₃ OD) δ7.48 (s, 1 H), 3.47 (s, 2 H), 2.20 (s, 3 H) ppm; MS m/e 231(M-H)⁻ ; HPLC (Column: Zorbax Rapid resolution C-18; flow rate: 2.5mL/min; solvent system: 0-100% B in 8 min. Solvent A: 10% MeOH-90%water-0.2%H₃ PO₄ ; Solvent B: 90% MeOH-10% Water-0.2% H₃ PO₄ ; UV: 254nm): retention time 4.32 min.

H. Preparation of[[2(acetylamino)-5-thiazolyl]thio]-N-(2-oxobutyl)acetamide

A mixture of [[2-(acetylamino)-5-thiazolyl]thio]acetic acid (9.0 g, 38.8mmol), HOBT (5.94 g, 38.8 mmol) and ethyldimethylaminopropylcarbodiimidehydrochloride salt (11.16 g, 58.2 mmol) in DMF (50 mL) was stirred at 0°C. for 0.5 h. To this mixture was added 1-amino-2-butanone hydrochloride(5.27 g, 42.7 mmol) followed by triethylamine (15 mL, 107.5 mmol). Themixture was stirred at 0° C. for 0.5 h and at rt for 1 h. Water (200 mL)was added to the mixture and the product was extracted with methylenechloride containing 10% MeOH (5×100 mL). The methylene chloride extractwas dried over Na₂ SO₄ and concentrated. The residue was triturated withwater and the precipitated solid product was collected by filtration. Itwas dried to obtain the desired product (10.5 g, 90%), mp 195-196° C.

¹ H NMR (CDCl₃) δ7.53 (s, 1 H), 4.14 (s, 2 H), 3.46 (s, 2 H), 2.50 (q,J=7.6 Hz, 2 H), 2.25 (s, 3 H), 1.12 (t, J=7.6 Hz, 3 H); MS m/e 302(M+H)⁺. HPLC (Column: Zorbax Rapid resolution C-18; flow rate: 2.5ml/min; solvent system: 0-100% B in 8 min. Solvent A: 10% MeOH-90%water-0.2% H₃ PO₄ ; Solvent B: 90% MeOH-10% Water-0.2% H₃ PO₄ ; UV: 254nm): retention time 4.36 min.

I. Preparation ofN[5-[[(5-ethyl-2-oxazolyl)methyl]thio]-2-thiazolyl]acetamide

To a solution of[[2-(acetylamino)-5-thiazolyl]thio]-N-(2-oxobutyl)acetamide (10.5 g,34.8 mmol) in acetic anhydride (100 mL) was added conc. sulfuric acid(10 mL). The mixture was stirred at 55-60° C. for 2 h and sodium acetate(15 g, 0.18 mol) was added to the mixture. The mixture was concentratedin vacuo. To the residue was added cold water (100 mL). The precipitatedsolid was collected, washed with water and dried. It was purified by aflash column chromatography (SiO₂ ; methylene chloride: MeOH/100:5) toafford N-[5-[[(5-ethyl-2-oxazolyl)methyl]thio]-2-thiazolyl]acetamide(4.2 g, 43%) as a solid, mp 147-148° C. ¹ H NMR (CDCl₃) δ12.47 (s, 1 H),7.29 (s, 1 H), 6.61 (s, 1 H), 3.91 (s, 2 H), 2.64 (q, J=7.6 Hz, 2 H),2.25 (s, 3 H), 1.21 (t, J=7.6 Hz, 3 H) ppm; MS m/e 284 (M+H)⁺ ;

HPLC (Column: Zorbax Rapid resolution C-18; flow rate: 2.5 mL/min;solvent system: 0-100% B in 8 min. Solvent A: 10% MeOH-90% water-0.2% H₃PO₄ ; Solvent B: 90% MeOH-10% Water-0.2% H₃ PO₄ ; UV: 254 nm): retentiontime 6.50 min. ##STR11## A. Preparation of2-amino-5-[[(5-ethyl-2-oxazolyl)methyl]thio]-thiazole

A solution ofN-[5-[[(5-ethyl-2-oxazolyl)methyl]thio]-2-thiazolyl]acetamide (1.3 g,4.6 mmol) in 1 N hydrochloric acid (15 mL) was stirred at 80-90° C. for3 h. It was cooled to rt and the pH of the solution was adjusted to 7with sodium carbonate. The product was extracted with methylene chloride(3×10 mL). The combined extract was dried over Na₂ SO₄ and concentrated.The residue was triturated with ethyl ether and the precipitated solidwas collected to afford2-amino-5-[[(5-ethyl-2-oxazolyl)methyl]thio]-thiazole (610 mg, 55%) as asolid, mp 119-120° C. ¹ H NMR (CDCl₃) δ6.93 (s, 1 H), 6.61 (s, 1 H),5.41 (s, 2 H), 3.82 (s, 3 H), 2.62 (q, J=7.6 Hz, 2 H), 1.18 (t, J=7.6Hz, 3 H); MS m/e 242 (M+H)⁺ ;

HPLC (Column: Zorbax Rapid resolution C-18; flow rate: 2.5 mL/min;solvent system: 0-100% B in 8 min. Solvent A: 10% MeOH-90% water-0.2% H₃PO₄ ; Solvent B: 90% MeOH-10% Water-0.2% H₃ PO₄ ; UV: 254 nm): retentiontime 3.96 min.

B. Preparation ofN-[5-[[(5-ethyl-2oxazolyl)methyl]thio]-2-thiazolyl]benzamide

A mixture of 2-amino-5-[[(5-ethyl-2-oxazolyl)methyl]thio]-thiazole (48.2mg, 0.2 mmol), benzoyl chloride (24.4 mg, 0.21 mmol) and triethylamine(35 mg, 0.35 mmol) in methylene chloride (0.5 mL) was stirred at rt for10 min. The organic solution was washed with water and concentrated. Theresidue was purified by a flash column (SiO₂ ; hexanes: ethylacetate/2:1) to affordN-[5-[[(5-ethyl-2-oxazolyl)methyl]thio]-2-thiazolyl]benzamide (41 mg,59%) as a solid, mp 122-123° C. ¹ H NMR (CDCl₃) δ12.65 (s, 1 H), 7.96(m, 2 H), 7.61 (m,, 1 H), 7.49 (m, 2 H), 6.88 (s, 1 H), 6.56 (s, 1 H),3.93 (s, 2 H), 2.61 (q, J=7.6 Hz, 2 H), 1.20 (t, J=7.6 Hz, 3 H); MS m/e346 (M+H)⁺ ;

HPLC (Column: Zorbax Rapid resolution C-18; flow rate: 2.5 mL/min;solvent system: 0-100% B in 8 min. Solvent A: 10% MeOH-90% water-0.2% H₃PO₄ ; Solvent B: 90% MeOH-10% Water-0.2% H₃ PO₄ ; UV: 254 nm): retentiontime 7.94 min. ##STR12##

A mixture of 2-amino-6-[[(5-ethyl-2-oxazolyl)methyl]thio]-thiazole (24.1mg, 0.1 mmol), benzenesulfonyl chloride (19.4 mg, 0.11 mmol) andtriethylamine (22 mg, 0.21 mmol) in methylene chloride (0.3 mL) wasstirred at rt for 10 h. The product of the reaction mixture was purifiedby preparative HPLC (column: YMC pack ODSA S3 20×100 mm; method:gradient from 0% B to 100% B in 20 min and flow rate 20 mL/min; Uw: 254nm; solvent A: 10% MeOH-90% water-0.1% TFA; solvent B: 90% MeOH-10%water-0.1% TFA) to obtainN-[5-[[(5-ethyl-2-oxazolyl)methyl]thio]-2-thiazolyl]benzsulfoneamide(2.5 mg) as a solid after drying via lyophilization.

¹ H NMR (CDCl₃) δ7.88 (d, J=8.0 Hz, 1 H), (s, 2 H), 7.49 (m, 3 H), 6.89(s, 1 H), 6.64 (s, 1 H), 4.01 (s, 2 H), 2.68 (q, J=7.4 Hz, 2 H), 1.27(t, J=7.4 Hz, 3 H); MS m/e 382 (M+H)⁺ ;

HPLC (column: Zorbax Rapid resolution C-18; flow rate: 2.5 mL/min;solvent system: 0-100% B in 8 min. Solvent A: 10% MeOH-90% water-0.2% H₃PO₄ ; Solvent B: 90% MeOH-10% Water-0.2% H₃ PO₄ ; UW: 254 nm): retentiontime 6.84 min. ##STR13## A. Preparation of2-(bromomethyl)-4,5-dimethyloxazole

A mixture of 2,4,5-trimethyloxazole (0.50 mL, 4.3 mmol),N-bromosuccinimide (0.77 g, 4.3 mmol) and benzoyl peroxide (0.21 g, 0.86mmol) in carbon tetrachloride (4 mL) was heated at 76° C. under nitrogenatm for 3 hrs. After cooling to rt, the solid was removed by filtration.The filtrate solution was washed with saturated aqueous NaHCO₃ (20 mL)and concentrated. The residue was purified by flash columnchromatography (SiO₂ ; hexanes:ethyl acetate/4:1) to afford2-(bromomethyl)-4,5-dimethyloxazole (64 mg) as an yellow oil. ¹ H NMR(CDCl₃) 67 4.4 (s, 2 H), 2.25 (s, 3 H), 2.05 (s, 3 H).

B. Preparation ofN-[5-[[(4,5-dimethyl-2-oxazolyl)meihyl]thio]-2-thiazolyl]acetamide

N-[5-(Acetylthio)-2-thiazolyl]acetamide (0.050 g, 0.23 mmol) wasdissolved in dry THF (10 ml) and here potassiumtert-butoxide (1.0 Msolution in THF, 0.25 ml, 0.25 mmol) was added to the mixture. Thereaction mixture was stirred at rt for 15 min., and2-(bromomethyl)-4,5-dimethyloxazole (0.064 g, 0.34 mmol) was added tothis mixture. The reaction mixture was stirred at rt for 3 h andsaturated aqueous NaHCO₃ solution (20 mL) was added to the mixture. Theorganic layer was separated and the aqueous layer was extracted withdichloromethane (3×20 mL). The combined organic layers was concentrated.The residue was purified by flash column chromatography (SiO₂ ;methanol:dichloromethane/1:20) to affordN-[5-[[(4,5-dimethyl-2-oxazolyl)methyl]thio]-2-thiazolyl]acetamide (15mg, 23%) as a yellow solid.

¹ H NMR (CDCl₃) δ11.78 (s, 1 H), 7.38 (s, 1 H), 3.90 (s, 2 H), 2.30 (s,3H), 2.22 (s 3 H), 2.05 (s, 3 H); MS m/e 284 (M+H)⁺ ;

HPLC (Column: Zorbax Rapid resolution C-18; flow rate: 2.5 ml/min;solvent system: 0-100% B in 8 min. Solvent A: 10% CH₃ OH/90% H₂ O/0.2%H₃ PO₄ ; Solvent B: 90% CH₃ OH/10% H₂ O/0.2% H₃ PO₄ ; UV: 254 nm):retention time 5.87 min. ##STR14## A. Preparation of diazomethane

To a mixture of 15 ml of 40% aqueous KOH solution and 50 mL of diethylether at 0° C. was added 5 g (68 mmol) ofN-methyl-N'-nitro-N-nitrosoguanidine in portions with stirring. Theresulting mixture was stirred at 0° C. for 0.5 h. The organic phase wasdecanted into a dry flask and dried over solid KOH pellets to give 50 mLof diazomethane solution (ca 0.5 M, by titrating with acetic acid).

B. Preparation of 1-diazo-3,3-dimethyl-2-butanone

To the diazomethane solution at 0° C. was added a solution of 1.23 mL(1.21 g, 10 mmol, Aldrich) of trimethylacetyl chloride in 1 mL ofdiethyl ether dropwise with stirring. The resulting mixture was kept at0° C. for 16 h. The solution was sparged with argon to remove the excessdiazomethane and diethyl ether was removed under reduced pressure togive 1.33 g (10 mmol, 100%) of crude 1-diazo-3,3-dimethyl-2-butanone asa yellow liquid.

C. Preparation of 2-chloromethyl-5-t-butyloxazole

To a solution of 2 mL (2.3 g, 16 mmol) of boron trifluoride etherate in20 mL of chloroacetonitrile at 0° C. was added a solution of 1.33 g (10mmol) of 1-diazo-3,3-dimethyl-2-butanone in 5 mL of chloroacetonitriledropwise. The resulting solution was stirred at 0° C. for 0.5 h. Thereaction mixture was added to saturated aqueous sodium bicarbonatesolution to neutralize the acid and the product was extracted threetimes with dichloromethane. The combined extracts was dried (sodiumsulfate), concentrated and purified by flash column chromatography(Merck silic a, 25×200 mm, dichloromethane) to give 1.1 g of2-(chloromethyl)-5-t-butyloxazole as a yellow liquid (6.4 mmol, 64%overall from the acid chloride). ¹ H NMR δ (CDCl₃): 1.30 (s, 9 H), 4.58(s, 2 H), 6.68 (s, 1 H); MS 174 (M+H)⁺ ; TLC: R_(f) (silica gel,dichloromethane)=0.33;

HPLC: t_(R) (YMC S-3 ODS 4.6×50 mm rapid resolution; 2.5 ml/min,gradient 0-100% B over 8 min, Solvent A: 10% CH₃ OH90% H₂ O/0.2% H₃ PO₄; Solvent B: 90% CH₃ OH/10% H₂ O/0.2% H₃ PO₄ ; UV:254 nm)=6.5 min.

D. Preparation ofN-[5-[[(5-t-butyl-2-oxazolyl)methyl]thio]-2-thiazolyl]acetamide

To a solution of 50 mg (0.23 mmol, Applied Chemical Laboratory) ofN-[5-(acetylthio)-2-thiazolyl]acetamide in 10 mL of THF was added 0.25mL of potassium tert-butoxide solution (1 M solution, 0.25 mmol) at rtunder argon. The resulting suspension was stirred for 15 min at rt, thena solution of 59 mg of 2-(chhloromethyl)-5-t-butyloxazole (0.34 mmol) in1 mL of THF was added. The resulting mixture was stirred at ft for 16 h,concentrated under reduced pressure and purified by flash columnchromatography (silica gel, 25×200 mm, 1:1 EtOAc/hexanes followed by100% EtOAc) to give 44 mg (0.14 mmol, 61%) ofN-[5-[[(5-t-butyl-2-oxazolyl)methyl]thio]-2-thiazolyl]acetamide as awhite solid.

¹ H NMR δ (CDCl₃) 1.27 (s, 9 H), 2.27 (s, 3 H), 3.95 (s, 2 H), 6.59 (s,1 H), 7.31 (s, 1 H), 11.03 (broad s, 1 H); MS 312 (M+H)⁺ ;

TLC: R_(f) (silica gel, ethyl acetate)=0.53, UV;

HPLC: retention tim (YMC S-3 ODS 4.6×50 mm rapid resolution; 2.5 ml/min,gradient 0-100% B over 8 min, Solvent A: 10% CH₃ OH/90% H₂ O/0.2% H₃ PO₄; Solvent B: 90% CH₃ OH/10% H₂ O/0.2% H₃ PO₄ ; UV: 254 nm)=6.8 min.##STR15## A. PreparationofN-[(5-thiocyanato)-2-thiazoy]trifluoroacetamide (XVIII)

To a mixture of 5-thiocyanato-2-aminothiazole (30 mmol) and 2,6-lutidine(35 mmol) in tetrahydrofuran (25 mL) and dichloromethane (50 mL) at -78°C. under argon was slowly added trifluoroaceticanhydride (33 mmol).After addition, the mixture was allowed to warm up to rt and stirredovernight. The mixture was diluted with dichloromethane (100 mL), andthe organic solution was washed with 5% aqueous citric acid followed bybrine, dried over magnesium sulfate and passed through a pad of silicagel. The product containing eluent was concentrated to afford 5.3 g oflight brown solid. ¹ H -NMR (CDCl₃) δ12.4 (br, 1 H), 7.83 (s, 1 H).

B. Preparation of 4-hydroxymethyl-3-methoxyphenyloxy Merriffeld resin(XVI)

To the suspension of sodium hydride (11.7 g, 60% in mineral oil, 293mmol) in dimethylformamide (30 mL) at 0° C. under argon was slowly addeda solution of 4-hydroxy-3-methoxybenzyldehyde (44.5 g, 292.5 mmol) indimethylformamide (100 mL). To the resulting mixture Merrifield resin(1% DVB, from Advanced Chemtech, loading 1.24 mmol/g, 50 g, 62 mmol) andcatalytic amount of tetra-n-butylammonium idodide were added, and it washeated at 65° C. for a day. The resin was filtered, washed with water(2×), 50% dimethylformamide in water (3×), dimethylformamide (2×), andmethanol (5×), and dried in vacuo. The dried resin (15 g) was treatedwith sodium borohydride (3.4 g, 90 mmol) in tetrahydrofuran (50 mL) andehthanol (50 mL) overnight. The resin was filtered, washed with 50%dimethylformamide in water (3×), dimethylformamide (2×), methanol (2×),and dichloromethane (5×), and dried in vacuo.

C. Preparation of 4-chloromethyl-3-methoxyphenyloxy Merrifield resin(XVII)

To a solution of triphenylphosphine (17 g, 65 mmol) in dichloromethane(200 mL) at 0° C. was slowly added triphosgene (9.2 g, 31 mmol)portionwise over a period of 30 minutes. After addition, the reactionmixture was stirred at 0° C. for 10 minutes. The solvent was removed invacuo and the residue was redissolved in dichloromethane (200 mL). Tothis mixture was added 4-hydroxymethyl-3-methoxyphenyloxy Merrifieldresin (12 g). The resulting mixture was agitated for 4 h. The resin waswashed with dry dichloromethane (6×) and dried in vacuo.

D. Preparation of4-[N-[(5-thiocyanato)-2-thiazolytryfluoroacetamido]methyl]methoxyphenyloxyMerrifield resin (XIX)

A mixture of 4-chloromethyl-3-methoxyphenyloxy Merrifield resin (15 g),N-[(5-thiocyanato)-2-thiazolyl]trifluoroacetamide (14 g, 55.3 mmol) anddiisopropylethylamine (7.8 mL, 45 mmol) in dimethylformamide (50 mL) anddichloromethane (100 mL) was agitated overnight. The resin was washedwith dimethylformamide (2×), methanol (2×), dichloromethane (4×), anddried in uacuo.

E. Preparation of4-[[N-[(5-mercapto)-2-thiazolyl]trifluoroacetamido]methyl]-3-methoxyphenyloxyMerrifield resin (XX)

A mixture of4-[N-[(5-thiocyanato)-2-thiazolyltrifluoroacetamido]methyl]-3-methoxyphenyloxyMerrifield resin (XIX, 18.5 g) and dithiothreitol (12 g, 78 mmol) intetrahydrofuran (100 mL) and methanol (100 mL) was agitated overnight.The resin was washed with dimethylformamide (2×), methanol (2×),dichloromethane (4×), and dried in vacuo and stored under argon at -20°C.

F. Preparation of4-N-[5-[[[(5-t-butyl-2-oxazolyl)methyl]thio]-2-thiazolyl]trifloroacetamnido]methyl-3-methoxyphenyloxyMerrifield resin (XX)

A stream of argon was bubb led through a mixture4-[[N-[(5-Mercapto)-2-thiazolyl]trifluoroacetamido]methyl]-3-methoxyphenyloxyMerrifield resin (XX, 500 mg), halide (2.0 mmol) and1,8-diazabicyclo[5,4,0]undec-7-ene (DBU, 1.5 mmol) in dimethylformamide(3 mL) for 5 min., and the mixture was heated at 80° C. for 2 h. Theresin was washed with dimethylformamide (2×), methanol (2×),dichloromethane (4×), and dried in vacuo.

G. Preparation of4-N-[5-[[(5-t-butyl-2-oxazolyl)methyl]thio]-2-thiazolyl]methyl-3-methoxyphenyloxyMerrifield resin (XXII)

A mixture of4-N-[5-[[[(5-t-butyl-2-oxazolyl)methyl]thio]-2-thiazolyl]trifluoroacetamido]methyl-3-methoxyphenyloxyMerrifield resin (XXI, 500 mg ) and sodium borohydride (4 mmol) intetrahydrofuran (2 mL) and ethanol (2 mL) was agitated overnight. Theresin was washed with 50% dimethylformamide in water (2×),dimethylformamide (2×), methanol (2×), dichloromethane (4×), and driedin vacuo.

H. Preparation of4-N-[5-[[[(5-t-butyl-2-oxazolyl)methyl]thio]-2-thiazolyl]trimethylacetamido]methyl-3-methoxyphenyloxyMerrifield resin (XXIII)

A mixture of4-N-[5-[[(5-t-butyl-2-oxazolyl)methyl]thio]-2-thiazolyl]methyl-3-methoxyphenyloxyMerrifield resin (XXII, 100 mg), diisopropylethylamine (1.2 mmol) andtrimethylacetyl chloride (1 mmol) in dichloromethane (2 mL) in apolypropylene tube fitted with a polyethylene frit and a luer stopcockwas agitated overnight. The resin was washed with dimethylformamide(2×), methanol (2×), dichloromethane (4×), and used in the next stepwithout drying.

I. Preparation ofN-[5-[[(5-t-butyl-2-oxazolyl)methyl]thio]-2-thiazolyl]trimethylacetamide

4-N-[5-[[[(5-t-butyl-2-oxazolyl)methyl]thio]-2-thiazolyl]trimethylacetamido]methyl-3-methoxyphenyloxyMerrifield resin (XXIII) was treated with 60% trifluoroacetic acid indichloromethane (2 mL) in a polypropylene tube fitted with apolyethylene frit and a luer stopcock for 4 hours. The solution wasdecanted to a tube and the resin was washed with dichloromethane. Thecombined organic solution was concentrated in Speed Vac. The residue waspurified by preparative-HPLC to afford 11.3 mg of the desired product.

MS m/e 354 (M+H)⁺. ##STR16## A. Preparation of2-(2-chloroacetamido)-1-butanol

To a mixture of 2-amino-1-butanol (5.0 mL, 53 mmol) and triethyl amine(15.0 mL, 111 mmol) in dichloromethane (20 mL) at -70° C. was addedchloroacetyl chloride (4.6 mL, 58 mmol) dropwise. The reaction mixturewas stirred at -70° C. for 15 min. and then was allowed to warm to rt.It was diluted with EtOAc (50 mL) and the reaction was quenched byadding water (50 mL). The organic layer was separated and the aqueouslayer was extracted with EtOAc (3×30 mL). The combined organic layerswas concentrated to afford 2-(2-chloroacetamido)-1-butanol (8.6 g, 98%)as a brown solid. ¹ H NMR (CDCl₃) δ6.75 (bs, 1 H), 4.10 (s, 2 H), 4.08(dd, 1 H), 3.90 (m, 1 H), 3.68 (m, 2 H), 2.98 (bs, 1 H), 1.60 (m, 2 H),0.97 (t, 3 H).

B. Preparation of 2-(2-chloroacetamido)-1-butyraldehyde

To a solution of oxalyl chloride (14.5 mL, 29.0 mmol) in dichrolomethane(30 mL) at -78° C. DMSO (2.75 mL, 38.8 mmol) was added dropwise over 5min. After stirring for 10 min. at -78° C., here was added a solution of2-(2-chloroacetamido)-1-butanol (4.0 g, 24 mmol) in 20 mL ofdichrolomethane dropwise over 15 min. The reaction mixture was stirredfor 40 min. at -78° C. and here was added triethyl amine (9.4 mL, 68mmol) dropwise over 5 min. and the reaction mixture was allowed to warmto room temperature and stirred for 2 hrs. The solid was removed byfiltration and washed with EtOAc. The organic phase was washed with 1 NHCl (2×100 mL), saturated aqueous NaHCO₃ (1×10 mL) and concentrated toafford 2-(2-chloroacetamido)-1-butyraldehyde (3.7 g, 95%) as a brownoil.

¹ H NMR (CDCl₃) δ9.60 (s, 1 H), 4.52 (q, 1 H), 4.12 (s, 2 H), 2.05 (m, 1H), 1.80 (m, 1 H), 0.97 (t, 3 H).

C. Preparation of 2-chloromethy-4-ethyloxazole

To a solution of 2-(2-chloroacetamido)-1-butyraldehyde (3.7 g, 23 mmol)in toluene (10 mL) was added POCl₃ (6.3 mL, 68 mmol). The reactionmixture was heated at 90° C. for 1 h under nitrogen. After cooling thereaction mixture to room temperature it was poured into ice water (10mL) and the pH of the solution was adjusted to 7 with 5 N NaOH. Thetoluene layer was separated and the aqueous layer was washed withdichloromethane (3×20 mL). The combined organic solution wasconcentrated and distilled to afford 2-chloromethy-4-ethyloxazole (1.1g, 31%) as a colorless liquid.

¹ H NMR (CDCl₃) δ7.30 (s, 1 H), 4.22 (s, 2 H), 2.50 (q, 2 H), 1.22 (t, 3H).

D. Preparation ofN-[5-[[(4-ethyl-2-oxazolyl)methyl]thiol]-2-thiazolyl]acetamide

To a solution of 2-acetylamino-5-thiazolylthiol (0.010 g, 0.050 mmol) indry THF (5 mL) was added potassium tert-butoxide (1.0 M solution in THF,0.060 mL, 0.060 mmol). The reaction mixture was stirred at roomtemperature for 15 min. and here was added 2-chloromethyl-4-ethyloxazole(0.015 g, 0.10 mmol). After 3 h, saturated aqueous NaHCO₃ solution (5mL) was added to the mixture. The organic layer was separated and theaqueous layer was washed with dichloromethane (3×10 mL). The combinedorganic layers was concentrated. The residue was purified by flashchromatography (SiO₂ ; methanol:dichloromethane/1:20) to affordN-[5-[[(4-ethyl-2-oxazolyl)methyl]thio]-2-thiazolyl]acetamide (5 mg,36%) as a white solid.

¹ H NMR (CDCl₃) δ11.25 (s, 1 H), 7.34 (s, 1 H), 7.31 (s, 1 H), 3.95 (s,2 H), 2.50 (q, 2 H), 2.27 (s, 3 H), 1.19 (t, 3 H); MS m/e 284 (M+H)⁺ ;HPLC (Column: Zorbax Rapid resolution C-18; flow rate: 2.5 ml/min;solvent system: 0-100% B in 8 min. Solvent A: 10% CH₃ OH/90% H₂ O/0.2%H₃ PO₄ ; Solvent B: 90% CH₃ OH/10% H₂ O/0.2% H₃ PO₄ ; UV: 254 nm):retention time 6.14 min.

Using the procedures described herein or by modification of theprocedures described herein as known to one or ordinary skill in theart, the following additional compounds have been prepared and disclosedin Table 1:

                                      TABLE 1                                     __________________________________________________________________________    Example                                                                            Structure                              Molecular Formula                                                                      (M                       __________________________________________________________________________                                                         + H)+                     8                                                                                  ##STR17##                             C9H11N3OS2                                                                             242                       9                                                                                  ##STR18##                             C12H15N3O2S2                                                                           298                       10                                                                                 ##STR19##                             C13H17N3O2S2                                                                           312                       11                                                                                 ##STR20##                             C10H13N3O3S3                                                                           320                       12                                                                                 ##STR21##                             C11H10F3N3O2S2                                                                         338                       13                                                                                 ##STR22##                             C14H19N3O2S2                                                                           326                       14                                                                                 ##STR23##                             C21H17N3O2S2                                                                           408                       15                                                                                 ##STR24##                             C17H24N4O2S2                                                                           381                       16                                                                                 ##STR25##                             C17H17N3O2S2                                                                           360                       17                                                                                 ##STR26##                             C15H19N3O2S2                                                                           338                       18                                                                                 ##STR27##                             C17H17N3O3S2                                                                           376                       19                                                                                 ##STR28##                             C17H23N3O2S2                                                                           366                       20                                                                                 ##STR29##                             C14H19N3O2S2                                                                           326                       21                                                                                 ##STR30##                             C13H15N3O2S2                                                                           310                       22                                                                                 ##STR31##                             C15H13N3O2S2                                                                           332                       23                                                                                 ##STR32##                             C13H11N3O2S2                                                                           306                       24                                                                                 ##STR33##                             C10H11N3O2S2                                                                           270                       25                                                                                 ##STR34##                             C12H15N3O2S2                                                                           298                       26                                                                                 ##STR35##                             C13H16BrN3O2S2                                                                         391                       27                                                                                 ##STR36##                             C15H12FN3O2S2                                                                          350                       28                                                                                 ##STR37##                             C13H15N3O4S2                                                                           342                       29                                                                                 ##STR38##                             C15H21N3O2S2                                                                           340                       30                                                                                 ##STR39##                             C19H21N3O2S2                                                                           388                       31                                                                                 ##STR40##                             C18H17N3O4S2                                                                           404                       32                                                                                 ##STR41##                             C15H19N3O4S2                                                                           370                       33                                                                                 ##STR42##                             C14H17N3O4S2                                                                           356                       34                                                                                 ##STR43##                             C16H19N3O3S2                                                                           366                       35                                                                                 ##STR44##                             C16H21N3O4S2                                                                           384                       36                                                                                 ##STR45##                             C15H19N3O4S2                                                                           370                       37                                                                                 ##STR46##                             C16H21N3O4S2                                                                           384                       38                                                                                 ##STR47##                             C18H17N3O4S2                                                                           404                       39                                                                                 ##STR48##                             C15H19N3O4S2                                                                           370                       40                                                                                 ##STR49##                             C16H14FN3O2S2                                                                          364                       41                                                                                 ##STR50##                             C16H14ClN3O2S2                                                                         380                       42                                                                                 ##STR51##                             C16H13Cl2N3O2S2                                                                        415                       43                                                                                 ##STR52##                             C18H19N3O4S2                                                                           406                       44                                                                                 ##STR53##                             C18H19N3O4S2                                                                           406                       45                                                                                 ##STR54##                             C18H19N3O4S2                                                                           406                       46                                                                                 ##STR55##                             C18H19N3O2S2                                                                           374                       47                                                                                 ##STR56##                             C18H20N4O2S2                                                                           503                       48                                                                                 ##STR57##                             C17H17N3O2S2                                                                           360                       49                                                                                 ##STR58##                             C18H19N3O2S2                                                                           374                       50                                                                                 ##STR59##                             C18H19N3O2S2                                                                           374                       51                                                                                 ##STR60##                             C18H20N4O2S2                                                                           503                       52                                                                                 ##STR61##                             C18H20N4O2S2                                                                           503                       53                                                                                 ##STR62##                             C19H16N4O2S2                                                                           511                       54                                                                                 ##STR63##                             C18H16N4O2S2                                                                           499                       55                                                                                 ##STR64##                             C18H16N4O2S2                                                                           499                       56                                                                                 ##STR65##                             C16H13F2N3O2S2                                                                         382                       57                                                                                 ##STR66##                             C17H15ClFN3O2S2                                                                        412                       58                                                                                 ##STR67##                             C19H19N3O4S2                                                                           418                       59                                                                                 ##STR68##                             C18H16F3N3O2S2                                                                         428                       60                                                                                 ##STR69##                             C17H16FN3O2S2                                                                          378                       61                                                                                 ##STR70##                             C17H16N4O4S2                                                                           405                       62                                                                                 ##STR71##                             C17H16N4O4S2                                                                           405                       63                                                                                 ##STR72##                             C19H21N3O4S2                                                                           420                       64                                                                                 ##STR73##                             C19H17N3O3S2                                                                           400                       65                                                                                 ##STR74##                             C12H15N3O3S2                                                                           314                       66                                                                                 ##STR75##                             C13H17N3O3S2                                                                           328                       67                                                                                 ##STR76##                             C15H14N4O2S2                                                                           461                       68                                                                                 ##STR77##                             C16H19N3O2S2                                                                           350                       69                                                                                 ##STR78##                             C15H17N5O2S2                                                                           364                       70                                                                                 ##STR79##                             C13H14F3N3O2S2                                                                         366                       71                                                                                 ##STR80##                             C15H15N3O2S3                                                                           366                       72                                                                                 ##STR81##                             C17H23N3O2S2                                                                           366                       73                                                                                 ##STR82##                             C16H16N4O2S2                                                                           475                       74                                                                                 ##STR83##                             C12H16N4O2S2                                                                           427                       75                                                                                 ##STR84##                             C18H19N3O3S2                                                                           390                       76                                                                                 ##STR85##                             C18H18N4O3S2                                                                           403                       77                                                                                 ##STR86##                             C22H19N3O3S2                                                                           438                       78                                                                                 ##STR87##                             C17H17N3O3S2                                                                           376                       79                                                                                 ##STR88##                             C22H19N3O2S2                                                                           422                       80                                                                                 ##STR89##                             C16H14ClN3O2S2                                                                         380                       81                                                                                 ##STR90##                             C17H17N3O3S2                                                                           376                       82                                                                                 ##STR91##                             C16H14ClN3O2S2                                                                         380                       83                                                                                 ##STR92##                             C17H17N3O3S2                                                                           376                       84                                                                                 ##STR93##                             C17H15N3O4S2                                                                           390                       85                                                                                 ##STR94##                             C17H14N4O2S3                                                                           403                       86                                                                                 ##STR95##                             C17H16ClN3O2S2                                                                         394                       87                                                                                 ##STR96##                             C18H19N3O3S2                                                                           390                       88                                                                                 ##STR97##                             C19H19N3O2S2                                                                           386                       89                                                                                 ##STR98##                             C21H23N3O2S2                                                                           414                       90                                                                                 ##STR99##                             C17H16ClN3O2S2                                                                         394                       91                                                                                 ##STR100##                            C18H19N3O3S2                                                                           390                       92                                                                                 ##STR101##                            C17H16ClN3O2S2                                                                         394                       93                                                                                 ##STR102##                            C18H17N3O4S2                                                                           404                       94                                                                                 ##STR103##                            C25H22N4O2S2                                                                           589                       95                                                                                 ##STR104##                            C14H17N3O3S2                                                                           340                       96                                                                                 ##STR105##                            C14H17N3O3S2                                                                           340                       97                                                                                 ##STR106##                            C15H14N4O2S2                                                                           461                       98                                                                                 ##STR107##                            C16H21N3O2S2                                                                           352                       99                                                                                 ##STR108##                            C18H17N3O3S2                                                                           388                      100                                                                                 ##STR109##                            C16H16N4O2S2                                                                           475                      101                                                                                 ##STR110##                            C19H18N4O2S2                                                                           513                      102                                                                                 ##STR111##                            C17H14N4O2S2                                                                           371                      103                                                                                 ##STR112##                            C20H17N3O2S2                                                                           396                      104                                                                                 ##STR113##                            C21H18N4O3S2                                                                           553                      105                                                                                 ##STR114##                            C23H21N3O3S2                                                                           452                      106                                                                                 ##STR115##                            C20H21N3O2S2                                                                           400                      107                                                                                 ##STR116##                            C22H23N3O3S2                                                                           442                      108                                                                                 ##STR117##                            C17H15N5O2S2                                                                           500                      109                                                                                 ##STR118##                            C18H18N4O3S2                                                                           403                      110                                                                                 ##STR119##                            C17H17N5O2S3                                                                           420                      111                                                                                 ##STR120##                            C17H16BrN3O2S2                                                                         439                      112                                                                                 ##STR121##                            C17H16FN3O2S2                                                                          378                      113                                                                                 ##STR122##                            C17H15Cl2N3O2S2                                                                        429                      114                                                                                 ##STR123##                            C17H15N3O3S2                                                                           374                      115                                                                                 ##STR124##                            C18H19N3O2S2                                                                           374                      116                                                                                 ##STR125##                            C17H16BrN3O2S2                                                                         439                      117                                                                                 ##STR126##                            C18H19N3O2S2                                                                           374                      118                                                                                 ##STR127##                            C17H16BrN3O2S2                                                                         439                      119                                                                                 ##STR128##                            C18H19N3O2S2                                                                           374                      120                                                                                 ##STR129##                            C18H16N4O2S2                                                                           499                      121                                                                                 ##STR130##                            C17H15F2N3O2S2                                                                         396                      122                                                                                 ##STR131##                            C17H15F2N3O2S2                                                                         396                      123                                                                                 ##STR132##                            C17H15F2N3O2S2                                                                         396                      124                                                                                 ##STR133##                            C20H23N3O2S2                                                                           402                      125                                                                                 ##STR134##                            C18H19N3O3S2                                                                           390                      126                                                                                 ##STR135##                            C17H18N4O2S2                                                                           489                      127                                                                                 ##STR136##                            C14H17N3O2S2                                                                           324                      128                                                                                 ##STR137##                            C13H17N3O3S2                                                                           328                      129                                                                                 ##STR138##                            C14H13N3O3S2                                                                           336                      130                                                                                 ##STR139##                            C14H13N3O3S2                                                                           336                      131                                                                                 ##STR140##                            C15H21N3O2S2                                                                           340                      132                                                                                 ##STR141##                            C15H21N3O2S2                                                                           340                      133                                                                                 ##STR142##                            C15H21N3O2S2                                                                           340                      134                                                                                 ##STR143##                            C15H21N3O2S2                                                                           340                      135                                                                                 ##STR144##                            C14H13N5O2S2                                                                           348                      136                                                                                 ##STR145##                            C15H15N3O3S2                                                                           350                      137                                                                                 ##STR146##                            C14H17N3O4S2                                                                           356                      138                                                                                 ##STR147##                            C14H15N5O2S2                                                                           464                      139                                                                                 ##STR148##                            C19H21N3O2S2                                                                           388                      140                                                                                 ##STR149##                            C16H16N4O2S2                                                                           475                      141                                                                                 ##STR150##                            C19H18N4O2S2                                                                           513                      142                                                                                 ##STR151##                            C15H17N5O2S2                                                                           478                      143                                                                                 ##STR152##                            C19H21N3O3S2                                                                           404                      144                                                                                 ##STR153##                            C12H16N4O2S2                                                                           427                      145                                                                                 ##STR154##                            C20H20N4O2S2                                                                           527                      146                                                                                 ##STR155##                            C13H18N4O2S2                                                                           441                      147                                                                                 ##STR156##                            C19H18N4O4S2                                                                           431                      148                                                                                 ##STR157##                            C14H17N3O2S2                                                                           324                      149                                                                                 ##STR158##                            C15H21N3O2S2                                                                           340                      150                                                                                 ##STR159##                            C13H14N4O3S3                                                                           371                      151                                                                                 ##STR160##                            C15H20N4O2S2                                                                           467                      152                                                                                 ##STR161##                            C17H22N4O3S2                                                                           395                      153                                                                                 ##STR162##                            C14H17N3O2S2                                                                           324                      154                                                                                 ##STR163##                            C19H18N4O2S2                                                                           513                      155                                                                                 ##STR164##                            C14H19N3O2S2                                                                           326                      156                                                                                 ##STR165##                            C19H21N3O2S2                                                                           388                      157                                                                                 ##STR166##                            C16H13Cl2N3O2S2                                                                        415                      158                                                                                 ##STR167##                            C17H17N3O2S2                                                                           360                      159                                                                                 ##STR168##                            C16H12F3N3O2S2                                                                         400                      160                                                                                 ##STR169##                            C20H18N4O2S2                                                                           525                      161                                                                                 ##STR170##                            C20H18N4O2S2                                                                           525                      162                                                                                 ##STR171##                            C19H21N3O2S2                                                                           388                      163                                                                                 ##STR172##                            C19H21N3O4S2                                                                           420                      164                                                                                 ##STR173##                            C17H16FN3O2S2                                                                          378                      165                                                                                 ##STR174##                            C20H23N3O5S2                                                                           450                      166                                                                                 ##STR175##                            C18H16F3N3O2S2                                                                         428                      167                                                                                 ##STR176##                            C19H21N3O2S2                                                                           388                      168                                                                                 ##STR177##                            C19H21N3O2S2                                                                           388                      169                                                                                 ##STR178##                            C18H19N3O2S2                                                                           374                      170                                                                                 ##STR179##                            C17H17N3O3S2                                                                           376                      171                                                                                 ##STR180##                            C19H22N4O2S2                                                                           517                      172                                                                                 ##STR181##                            C19H21N3O2S2                                                                           388                      173                                                                                 ##STR182##                            C19H21N3O4S2                                                                           420                      174                                                                                 ##STR183##                            C17H15F2N3O2S2                                                                         396                      175                                                                                 ##STR184##                            C14H15N5O2S2                                                                           350                      176                                                                                 ##STR185##                            C15H14N3O2S2                                                                           461                      177                                                                                 ##STR186##                            C18H19N3O3S2                                                                           390                      178                                                                                 ##STR187##                            C18H19N3O4S2                                                                           406                      179                                                                                 ##STR188##                            C22H19N3O3S2                                                                           438                      180                                                                                 ##STR189##                            C17H16N4O4S2                                                                           405                      181                                                                                 ##STR190##                            C20H23N3O2S2                                                                           402                      182                                                                                 ##STR191##                            C23H21N3O2S2                                                                           436                      183                                                                                 ##STR192##                            C24H23N3O2S2                                                                           450                      184                                                                                 ##STR193##                            C23H21N3O2S2                                                                           436                      185                                                                                 ##STR194##                            C - 21H19N3O2S2                                                                        410                      186                                                                                 ##STR195##                            C21H19N3O2S2                                                                           410                      187                                                                                 ##STR196##                            C17H15Cl2N3O2S2                                                                        429                      188                                                                                 ##STR197##                            C19H21N3O4S2                                                                           420                      189                                                                                 ##STR198##                            C18H19N3O2S2                                                                           374                      190                                                                                 ##STR199##                            C19H18F3N3O3S2                                                                         458                      191                                                                                 ##STR200##                            C22H27N3O2S2                                                                           430                      192                                                                                 ##STR201##                            C18H19N3O2S2                                                                           374                      193                                                                                 ##STR202##                            C12H15N3O2S2                                                                           298                      194                                                                                 ##STR203##                            C18H26N4O4S2                                                                           427                      195                                                                                 ##STR204##                            C12H13N3O4S2                                                                           328                      196                                                                                 ##STR205##                            C11H13N3O4S2                                                                           316                      197                                                                                 ##STR206##                            C11H13N3O3S2                                                                           300                      198                                                                                 ##STR207##                            C11H15N3OS2                                                                            270                      199                                                                                 ##STR208##                            C10H13N3OS2                                                                            256                      200                                                                                 ##STR209##                            C17H16N4O4S2                                                                           405                      201                                                                                 ##STR210##                            C19H20N4O2S2                                                                           401                      202                                                                                 ##STR211##                            C16H15BrN4O2S2                                                                         440                      203                                                                                 ##STR212##                            C17H16N6O2S2                                                                           515                      204                                                                                 ##STR213##                            C19H17N5O2S2                                                                           526                      205                                                                                 ##STR214##                            C20H23N5O3S2                                                                           560                      206                                                                                 ##STR215##                            C16H16N4O2S2                                                                           361                      207                                                                                 ##STR216##                            C16H14F2N4O2S2                                                                         397                      208                                                                                 ##STR217##                            C16H15ClN4O2S2                                                                         395                      209                                                                                 ##STR218##                            C17H18N4O3S2                                                                           391                      210                                                                                 ##STR219##                            C17H18N4O2S2                                                                           375                      211                                                                                 ##STR220##                            C16H15BrN4O2S2                                                                         440                      212                                                                                 ##STR221##                            C16H15ClN4O2S2                                                                         395                      213                                                                                 ##STR222##                            C16H14Cl2N4O2S2                                                                        430                      214                                                                                 ##STR223##                            C17H17ClN4O3S2                                                                         425                      215                                                                                 ##STR224##                            C17H18N4O3S2                                                                           391                      216                                                                                 ##STR225##                            C16H15BrN4O2S2                                                                         440                      217                                                                                 ##STR226##                            C16H15FN4O2S2                                                                          379                      218                                                                                 ##STR227##                            C17H18N4O2S2                                                                           375                      219                                                                                 ##STR228##                            C17H18N4O3S2                                                                           391                      220                                                                                 ##STR229##                            C16H15ClN4O2S2                                                                         395                      221                                                                                 ##STR230##                            C18H19N5O3S2                                                                           418                      222                                                                                 ##STR231##                            C17H18N4O3S2                                                                           391                      223                                                                                 ##STR232##                            C18H21N5O2S2                                                                           518                      224                                                                                 ##STR233##                            C16H15FN4O2S2                                                                          379                      225                                                                                 ##STR234##                            C16H15FN4O2S2                                                                          379                      226                                                                                 ##STR235##                            C17H18N4O2S2                                                                           375                      227                                                                                 ##STR236##                            C17H17N5O3S2                                                                           404                      228                                                                                 ##STR237##                            C17H15N5O2S3                                                                           418                      229                                                                                 ##STR238##                            C17H16N6O2S2                                                                           401                      230                                                                                 ##STR239##                            C16H15N7O2S2                                                                           402                      231                                                                                 ##STR240##                            C16H17N5O2S2                                                                           490                      232                                                                                 ##STR241##                            C15H20N4O2S2                                                                           353                      233                                                                                 ##STR242##                            C17H17ClN4O2S2                                                                         409                      234                                                                                 ##STR243##                            C17H19N5O2S2                                                                           504                      235                                                                                 ##STR244##                            C17H19N5O2S2                                                                           504                      236                                                                                 ##STR245##                            C19H18N6O2S3                                                                           459                      237                                                                                 ##STR246##                            C15H16N4O2S3                                                                           381                      238                                                                                 ##STR247##                            C15H20N4O3S2                                                                           369                      239                                                                                 ##STR248##                            C16H20N6O2S2                                                                           507                      240                                                                                 ##STR249##                            C18H25N5O4S2                                                                           440                      241                                                                                 ##STR250##                            C17H24N4O2S2                                                                           381                      242                                                                                 ##STR251##                            C18H20N4O2S2                                                                           389                      243                                                                                 ##STR252##                            C17H18N4O2S2                                                                           375                      244                                                                                 ##STR253##                            C18H20N4O2S2                                                                           389                      245                                                                                 ##STR254##                            C19H22N4O2S2                                                                           403                      246                                                                                 ##STR255##                            C17H19N5O2S2                                                                           504                      247                                                                                 ##STR256##                            C17H17ClN4O2S2                                                                         409                      248                                                                                 ##STR257##                            C16H17N5O2S2                                                                           490                      249                                                                                 ##STR258##                            C17H25N5O2S2                                                                           510                      250                                                                                 ##STR259##                            C16H17N5O2S2                                                                           490                      251                                                                                 ##STR260##                            C17H25N5O2S2                                                                           510                      252                                                                                 ##STR261##                            C18H20N4O2S2                                                                           389                      253                                                                                 ##STR262##                            C15H16N4O3S2                                                                           365                      254                                                                                 ##STR263##                            C17H16F2N4O2S2                                                                         411                      255                                                                                 ##STR264##                            C15H22N4O2S2                                                                           355                      256                                                                                 ##STR265##                            C14H18N4O2S2                                                                           339                      257                                                                                 ##STR266##                            C14H20N4O2S2                                                                           341                      258                                                                                 ##STR267##                            C15H22N4O2S2                                                                           355                      259                                                                                 ##STR268##                            C17H17ClN4O2S2                                                                         409                      260                                                                                 ##STR269##                            C18H20N4O2S2                                                                           389                      261                                                                                 ##STR270##                            C18H20N4O3S2                                                                           405                      262                                                                                 ##STR271##                            C18H20N4O3S2                                                                           405                      263                                                                                 ##STR272##                            C18H20N4O3S2                                                                           405                      264                                                                                 ##STR273##                            C16H22N4O3S2                                                                           341                      265                                                                                 ##STR274##                            C14H20N4O2S2                                                                           512                      266                                                                                 ##STR275##                            C17H27N5O2S2                                                                           353                      267                                                                                 ##STR276##                            C16H22N4O3S2                                                                           425                      268                                                                                 ##STR277##                            C18H24N4O4S2                                                                           401                      269                                                                                 ##STR278##                            C19H20N4O2S2                                                                           383                      270                                                                                 ##STR279##                            C17H26N4O2S2                                                                           355                      271                                                                                 ##STR280##                            C15H22N4O2S2                                                                           433                      272                                                                                 ##STR281##                            C19H20N4O4S2                                                                           512                      273                                                                                 ##STR282##                            C16H21N5O3S2                                                                           353                      274                                                                                 ##STR283##                            C15H20N4O3S2                                                                           367                      275                                                                                 ##STR284##                            C16H22N4O2S2                                                                           389                      276                                                                                 ##STR285##                            C16H21N5O3S2                                                                           425                      277                                                                                 ##STR286##                            C18H24N4O4S2                                                                           369                      278                                                                                 ##STR287##                            C13H18N4O2S2                                                                           465                      279                                                                                 ##STR288##                            C13H14N6O2S2                                                                           493                      280                                                                                 ##STR289##                            C15H18N6O2S2                                                                           466                      281                                                                                 ##STR290##                            C12H13N7O2S2                                                                           366                      282                                                                                 ##STR291##                            C14H15N5O3S2                                                                           366                      283                                                                                 ##STR292##                            C13H14N6O2S3                                                                           409                      284                                                                                 ##STR293##                            C17H17ClN4O2S2                                                                         387                      285                                                                                 ##STR294##                            C18H18N4O2S2                                                                           375                      286                                                                                 ##STR295##                            C17H18N4O2S2                                                                           405                      287                                                                                 ##STR296##                            C18H20N4O3S2                                                                           389                      288                                                                                 ##STR297##                            C17H16F2N4O2S2                                                                         490                      289                                                                                 ##STR298##                            C16H17N5O2S2                                                                           476                      290                                                                                 ##STR299##                            C15H15N5O2S2                                                                           510                      291                                                                                 ##STR300##                            C15H14ClN5O2S2                                                                         490                      292                                                                                 ##STR301##                            C16H17N5O2S2                                                                           490                      293                                                                                 ##STR302##                            C16H17N5O2S2                                                                           476                      294                                                                                 ##STR303##                            C15H15N5O2S2                                                                           526                      295                                                                                 ##STR304##                            C15H15N5O2S2                                                                           540                      296                                                                                 ##STR305##                            C18H29N5O2S2                                                                           526                      297                                                                                 ##STR306##                            C14H19N3O2S2                                                                           326                      298                                                                                 ##STR307##                            C21H23N3O2S2                                                                           414                      299                                                                                 ##STR308##                            C19H25N3O2S2                                                                           392                      300                                                                                 ##STR309##                            C22H21N3O2S2                                                                           424                      301                                                                                 ##STR310##                            C22H21N3O2S2                                                                           424                      302                                                                                 ##STR311##                            C15H19N3O2S2                                                                           338                      303                                                                                 ##STR312##                            C16H23N3O2S2                                                                           354                      304                                                                                 ##STR313##                            C18H19N3O2S2                                                                           374                      305                                                                                 ##STR314##                            C18H16N4O2S2                                                                           385                      306                                                                                 ##STR315##                            C20H23N3O2S2                                                                           402                      307                                                                                 ##STR316##                            C18H17F2N3O2S2                                                                         410                      308                                                                                 ##STR317##                            C21H23N3O2S2                                                                           414                      309                                                                                 ##STR318##                            C18H16N4O2S3                                                                           417                      310                                                                                 ##STR319##                            C19H19N3O4S2                                                                           418                      311                                                                                 ##STR320##                            C20H23N3O3S2                                                                           418                      312                                                                                 ##STR321##                            C18H18N4O4S2                                                                           419                      313                                                                                 ##STR322##                            C18H18N4O4S2                                                                           419                      314                                                                                 ##STR323##                            C18H18N4O4S2                                                                           419                      315                                                                                 ##STR324##                            C19H21N3O4S2                                                                           420                      316                                                                                 ##STR325##                            C19H21N3O4S2                                                                           420                      317                                                                                 ##STR326##                            C18H19N5O2S3                                                                           434                      318                                                                                 ##STR327##                            C18H19N5O2S3                                                                           434                      319                                                                                 ##STR328##                            C19H18F3N3O2S2                                                                         442                      320                                                                                 ##STR329##                            C18H18BrN3O2S2                                                                         453                      321                                                                                 ##STR330##                            C21H25N3O5S2                                                                           464                      322                                                                                 ##STR331##                            C23H28N4O4S2                                                                           489                      323                                                                                 ##STR332##                            C20H21N3O2S2                                                                           400                      324                                                                                 ##STR333##                            C18H25N3O2S2                                                                           380                      325                                                                                 ##STR334##                            C19H21N3O2S2                                                                           388                      326                                                                                 ##STR335##                            C27H26N4O3S2                                                                           519                      327                                                                                 ##STR336##                            C19H21N3O3S2                                                                           404                      328                                                                                 ##STR337##                            C20H23N3O2S2                                                                           402                      329                                                                                 ##STR338##                            C19H21N3O2S2                                                                           388                      330                                                                                 ##STR339##                            C19H21N3O2S2                                                                           388                      331                                                                                 ##STR340##                            C19H21N3O3S2                                                                           404                      332                                                                                 ##STR341##                            C26H28N4O4S3                                                                           557                      333                                                                                 ##STR342##                            C19H27N3O2S2                                                                           394                      334                                                                                 ##STR343##                            C22H22N4O3S2                                                                           455                      335                                                                                 ##STR344##                            C22H25N3O4S2                                                                           460                      336                                                                                 ##STR345##                            C20H21N3O3S2                                                                           416                      337                                                                                 ##STR346##                            C15H19N3O4S2                                                                           370                      338                                                                                 ##STR347##                            C20H18F3N3O2S2                                                                         454                      339                                                                                 ##STR348##                            C24H26N4O3S2                                                                           483                      340                                                                                 ##STR349##                            C18H19N3O3S2                                                                           390                      341                                                                                 ##STR350##                            C18H19N3O3S2                                                                           390                      342                                                                                 ##STR351##                            C20H20N4O2S2                                                                           413                      343                                                                                 ##STR352##                            C18H19N3O2S2                                                                           374                      344                                                                                 ##STR353##                            C19H18N4O2S2                                                                           399                      345                                                                                 ##STR354##                            C17H18N4O2S2                                                                           489                      346                                                                                 ##STR355##                            C17H18N4O2S2                                                                           489                      347                                                                                 ##STR356##                            C20H20N4O2S2                                                                           413                      348                                                                                 ##STR357##                            C20H24N4O2S2                                                                           531                      349                                                                                 ##STR358##                            C21H22N4O2S2                                                                           427                      350                                                                                 ##STR359##                            C16H17N5O4S2                                                                           408                      351                                                                                 ##STR360##                            C19H18N6O2S3                                                                           687                      352                                                                                 ##STR361##                            C11H15N3OS2                                                                            270                      353                                                                                 ##STR362##                            C17H19N3OS2                                                                            346                      354                                                                                 ##STR363##                            C13H19N3OS2                                                                            298                      355                                                                                 ##STR364##                            C22H25N3O2S2                                                                           428                      356                                                                                 ##STR365##                            C20H27N3O2S2                                                                           406                      357                                                                                 ##STR366##                            C23H23N3O2S2                                                                           438                      358                                                                                 ##STR367##                            C23H23N3O2S2                                                                           438                      359                                                                                 ##STR368##                            C16H21N3O2S2                                                                           352                      360                                                                                 ##STR369##                            C17H25N3O2S2                                                                           368                      361                                                                                 ##STR370##                            C19H21N3O2S2                                                                           388                      362                                                                                 ##STR371##                            C19H18N4O2S2                                                                           399                      363                                                                                 ##STR372##                            C21H25N3O2S2                                                                           416                      364                                                                                 ##STR373##                            C19H19F2N3O2S2                                                                         424                      365                                                                                 ##STR374##                            C22H25N3O2S2                                                                           428                      366                                                                                 ##STR375##                            C19H18N4O2S3                                                                           431                      367                                                                                 ##STR376##                            C20H21N3O4S2                                                                           432                      368                                                                                 ##STR377##                            C21H25N3O3S2                                                                           432                      369                                                                                 ##STR378##                            C19H20N4O4S2                                                                           433                      370                                                                                 ##STR379##                            C19H20N4O4S2                                                                           433                      371                                                                                 ##STR380##                            C20H23N3O4S2                                                                           434                      372                                                                                 ##STR381##                            C20H23N3O4S2                                                                           434                      373                                                                                 ##STR382##                            C19H21N5O2S3                                                                           448                      374                                                                                 ##STR383##                            C19H21N5O2S3                                                                           448                      375                                                                                 ##STR384##                            C19H20BrN3O2S2                                                                         467                      376                                                                                 ##STR385##                            C22H27N3O5S2                                                                           478                      377                                                                                 ##STR386##                            C24H30N4O4S2                                                                           503                      378                                                                                 ##STR387##                            C21H23N3O2S2                                                                           414                      379                                                                                 ##STR388##                            C19H27N3O2S2                                                                           394                      380                                                                                 ##STR389##                            C20H23N3O2S2                                                                           402                      381                                                                                 ##STR390##                            C28H28N4O3S2                                                                           533                      382                                                                                 ##STR391##                            C20H23N3O3S2                                                                           418                      383                                                                                 ##STR392##                            C19H20N4O5S2                                                                           449                      384                                                                                 ##STR393##                            C21H25N3O2S2                                                                           416                      385                                                                                 ##STR394##                            C25H27N3O3S2                                                                           482                      386                                                                                 ##STR395##                            C20H23N3O2S2                                                                           402                      387                                                                                 ##STR396##                            C20H23N3O2S2                                                                           402                      388                                                                                 ##STR397##                            C20H23N3O3S2                                                                           418                      389                                                                                 ##STR398##                            C18H20N4O2S2                                                                           503                      390                                                                                 ##STR399##                            C27H30N4O4S3                                                                           571                      391                                                                                 ##STR400##                            C20H29N3O2S2                                                                           408                      392                                                                                 ##STR401##                            C23H24N4O3S2                                                                           469                      393                                                                                 ##STR402##                            C23H27N3O4S2                                                                           474                      394                                                                                 ##STR403##                            C21H23N3O3S2                                                                           430                      395                                                                                 ##STR404##                            C16H21N3O4S2                                                                           384                      396                                                                                 ##STR405##                            C21H20F3N3O2S2                                                                         468                      397                                                                                 ##STR406##                            C25H28N4O3S2                                                                           497                      398                                                                                 ##STR407##                            C19H21N3O3S2                                                                           404                      399                                                                                 ##STR408##                            C21H22N4O2S2                                                                           427                      400                                                                                 ##STR409##                            C20H20N4O2S2                                                                           413                      401                                                                                 ##STR410##                            C18H20N4O2S2                                                                           503                      402                                                                                 ##STR411##                            C18H20N4O2S2                                                                           503                      403                                                                                 ##STR412##                            C21H22N4O2S2                                                                           427                      404                                                                                 ##STR413##                            C21H26N4O2S2                                                                           545                      405                                                                                 ##STR414##                            C22H24N4O2S2                                                                           441                      406                                                                                 ##STR415##                            C16H19N5O2S3                                                                           524                      407                                                                                 ##STR416##                            C20H23N3O3S2                                                                           418                      408                                                                                 ##STR417##                            C16H19N5O2S2                                                                           492                      409                                                                                 ##STR418##                            C17H19N5O4S2                                                                           422                      410                                                                                 ##STR419##                            C26H34N4O4S2                                                                           531                      411                                                                                 ##STR420##                            C24H30N4O4S2                                                                           503                      412                                                                                 ##STR421##                            C25H32N4O4S2                                                                           517                      413                                                                                 ##STR422##                            C21H26N4O2S2                                                                           545                      414                                                                                 ##STR423##                            C19H22N4O2S2                                                                           517                      415                                                                                 ##STR424##                            C20H24N4O2S2                                                                           531                      416                                                                                 ##STR425##                            C19H22N4O2S2                                                                           403                      417                                                                                 ##STR426##                            C16H14F2N4O2S2                                                                         397                      418                                                                                 ##STR427##                            C16H14Cl2N4O2S2                                                                        430                      419                                                                                 ##STR428##                            C18H20N4OS3                                                                            405                      420                                                                                 ##STR429##                            C16H14Cl2N4OS3                                                                         446                      421                                                                                 ##STR430##                            C21H23N3O2S2                                                                           414                      422                                                                                 ##STR431##                            C19H25N3O2S2                                                                           392                      423                                                                                 ##STR432##                            C22H21N3O2S2                                                                           424                      424                                                                                 ##STR433##                            C22H21N3O2S2                                                                           424                      425                                                                                 ##STR434##                            C15H19N3O2S2                                                                           338                      426                                                                                 ##STR435##                            C16H23N3O2S2                                                                           354                      427                                                                                 ##STR436##                            C18H19N3O2S2                                                                           374                      428                                                                                 ##STR437##                            C18H16N4O2S2                                                                           385                      429                                                                                 ##STR438##                            C20H23N3O2S2                                                                           402                      430                                                                                 ##STR439##                            C18H17F2N3O2S2                                                                         410                      431                                                                                 ##STR440##                            C21H23N3O2S2                                                                           414                      432                                                                                 ##STR441##                            C18H16N4O2S3                                                                           417                      433                                                                                 ##STR442##                            C19H19N3O4S2                                                                           418                      434                                                                                 ##STR443##                            C20H23N3O3S2                                                                           418                      435                                                                                 ##STR444##                            C18H18N4O4S2                                                                           419                      436                                                                                 ##STR445##                            C18H18N4O4S2                                                                           419                      437                                                                                 ##STR446##                            C18H18N4O4S2                                                                           419                      438                                                                                 ##STR447##                            C19H21N3O4S2                                                                           420                      439                                                                                 ##STR448##                            C19H21N3O4S2                                                                           420                      440                                                                                 ##STR449##                            C18H19N5O2S3                                                                           434                      441                                                                                 ##STR450##                            C18H19N5O2S3                                                                           434                      442                                                                                 ##STR451##                            C19H18F3N3O2S2                                                                         442                      443                                                                                 ##STR452##                            C18H18BrN3O2S2                                                                         453                      444                                                                                 ##STR453##                            C21H25N3O5S2                                                                           464                      445                                                                                 ##STR454##                            C23H28N4O4S2                                                                           489                      446                                                                                 ##STR455##                            C20H21N3O2S2                                                                           400                      447                                                                                 ##STR456##                            C18H25N3O2S2                                                                           380                      448                                                                                 ##STR457##                            C19H21N3O2S2                                                                           388                      449                                                                                 ##STR458##                            C27H26N4O3S2                                                                           519                      450                                                                                 ##STR459##                            C19H21N3O3S2                                                                           404                      451                                                                                 ##STR460##                            C18H18N4O5S2                                                                           435                      452                                                                                 ##STR461##                            C20H23N3O2S2                                                                           402                      453                                                                                 ##STR462##                            C24H25N3O3S2                                                                           468                      454                                                                                 ##STR463##                            C19H21N3O2S2                                                                           388                      455                                                                                 ##STR464##                            C19H21N3O2S2                                                                           388                      456                                                                                 ##STR465##                            C19H21N3O3S2                                                                           404                      457                                                                                 ##STR466##                            C17H18N4O2S2                                                                           489                      458                                                                                 ##STR467##                            C26H28N4O4S3                                                                           557                      459                                                                                 ##STR468##                            C19H27N3O2S2                                                                           394                      460                                                                                 ##STR469##                            C22H22N4O3S2                                                                           455                      461                                                                                 ##STR470##                            C22H25N3O4S2                                                                           460                      462                                                                                 ##STR471##                            C20H21N3O3S2                                                                           416                      463                                                                                 ##STR472##                            C15H19N3O4S2                                                                           370                      464                                                                                 ##STR473##                            C20H18F3N3O2S2                                                                         454                      465                                                                                 ##STR474##                            C24H26N4O3S2                                                                           483                      466                                                                                 ##STR475##                            C18H19N3O3S2                                                                           390                      467                                                                                 ##STR476##                            C18H19N3O3S2                                                                           390                      468                                                                                 ##STR477##                            C20H20N4O2S2                                                                           413                      469                                                                                 ##STR478##                            C15H21N3O2S2                                                                           340                      470                                                                                 ##STR479##                            C19H18N4O2S2                                                                           399                      471                                                                                 ##STR480##                            C17H18N4O2S2                                                                           489                      472                                                                                 ##STR481##                            C17H18N4O2S2                                                                           489                      473                                                                                 ##STR482##                            C20H20N4O2S2                                                                           413                      474                                                                                 ##STR483##                            C20H24N4O2S2                                                                           531                      475                                                                                 ##STR484##                            C21H22N4O2S2                                                                           427                      476                                                                                 ##STR485##                            C15H17N5O2S3                                                                           510                      477                                                                                 ##STR486##                            C19H21N3O3S2                                                                           404                      478                                                                                 ##STR487##                            C15H17N5O2S2                                                                           478                      479                                                                                 ##STR488##                            C16H17N5O4S2                                                                           408                      480                                                                                 ##STR489##                            C25H32N4O4S2                                                                           517                      481                                                                                 ##STR490##                            C23H28N4O4S2                                                                           489                      482                                                                                 ##STR491##                            C24H30N4O4S2                                                                           503                      483                                                                                 ##STR492##                            C19H18N6O2S3                                                                           459                      484                                                                                 ##STR493##                            C20H24N4O2S2                                                                           531                      485                                                                                 ##STR494##                            C18H20N4O2S2                                                                           503                      486                                                                                 ##STR495##                            C19H22N4O2S2                                                                           517                      487                                                                                 ##STR496##                            C13H18N4O2S2                                                                           363                      488                                                                                 ##STR497##                            C18H18F2N4O2S2                                                                         425                      489                                                                                 ##STR498##                            C18H18Cl2N4O2S2                                                                        458                      490                                                                                 ##STR499##                            C17H18N4O2S2                                                                           489                      491                                                                                 ##STR500##                            C18H20N4O2S2                                                                           389                      492                                                                                 ##STR501##                            C14H19N3O2S2                                                                           326                      493                                                                                 ##STR502##                            C16H21N3O2S2                                                                           352                      494                                                                                 ##STR503##                            C14H19N3O2S2                                                                           326                      495                                                                                 ##STR504##                            C14H19N3O2S2                                                                           326                      496                                                                                 ##STR505##                            C17H17N3O3S2                                                                           376                      497                                                                                 ##STR506##                            C18H19N3O3S2                                                                           390                      498                                                                                 ##STR507##                            C14H19N3O3S2                                                                           342                      499                                                                                 ##STR508##                            C21H31N3O3S2                                                                           438                      500                                                                                 ##STR509##                            C10H9BrN4O3S2                                                                          378                      501                                                                                 ##STR510##                            C19H22N4O3S2                                                                           419                      502                                                                                 ##STR511##                            C18H20N4O2S2                                                                           389                      503                                                                                 ##STR512##                            C19H22N4O2S2                                                                           403                      504                                                                                 ##STR513##                            C19H22N4O2S2                                                                           403                      505                                                                                 ##STR514##                            C15H21N3O3S2                                                                           356                      506                                                                                 ##STR515##                            C23H27N3O2S2                                                                           442                      507                                                                                 ##STR516##                            C21H29N3O2S2                                                                           420                      508                                                                                 ##STR517##                            C24H25N3O2S2                                                                           452                      509                                                                                 ##STR518##                            C24H25N3O2S2                                                                           452                      510                                                                                 ##STR519##                            C17H23N3O2S2                                                                           366                      511                                                                                 ##STR520##                            C18H27N3O2S2                                                                           382                      512                                                                                 ##STR521##                            C20H23N3O2S2                                                                           402                      513                                                                                 ##STR522##                            C20H20N4O2S2                                                                           413                      514                                                                                 ##STR523##                            C22H27N3O2S2                                                                           430                      515                                                                                 ##STR524##                            C20H21F2N3O2S2                                                                         438                      516                                                                                 ##STR525##                            C23H27N3O2S2                                                                           442                      517                                                                                 ##STR526##                            C20H20N4O2S3                                                                           445                      518                                                                                 ##STR527##                            C21H23N3O4S2                                                                           446                      519                                                                                 ##STR528##                            C22H27N3O3S2                                                                           446                      520                                                                                 ##STR529##                            C20H22N4O4S2                                                                           447                      521                                                                                 ##STR530##                            C20H22N4O4S2                                                                           447                      522                                                                                 ##STR531##                            C20H22N4O4S2                                                                           447                      523                                                                                 ##STR532##                            C21H25N3O3S2                                                                           432                      524                                                                                 ##STR533##                            C21H25N3O4S2                                                                           448                      525                                                                                 ##STR534##                            C20H23N5O2S3                                                                           462                      526                                                                                 ##STR535##                            C20H23N5O2S3                                                                           462                      527                                                                                 ##STR536##                            C21H22F3N3O2S2                                                                         470                      528                                                                                 ##STR537##                            C20H22BrN3O2S2                                                                         481                      529                                                                                 ##STR538##                            C23H29N3O5S2                                                                           492                      530                                                                                 ##STR539##                            C21H24N4O3S2                                                                           445                      531                                                                                 ##STR540##                            C22H25N3O4S2                                                                           460                      532                                                                                 ##STR541##                            C20H29N3O2S2                                                                           408                      533                                                                                 ##STR542##                            C21H25N3O2S2                                                                           416                      534                                                                                 ##STR543##                            C29H30N4O3S2                                                                           547                      535                                                                                 ##STR544##                            C22H27N3O3S2                                                                           446                      536                                                                                 ##STR545##                            C20H22N4O5S2                                                                           463                      537                                                                                 ##STR546##                            C22H27N3O2S2                                                                           430                      538                                                                                 ##STR547##                            C26H29N3O3S2                                                                           496                      539                                                                                 ##STR548##                            C21H25N3O2S2                                                                           416                      540                                                                                 ##STR549##                            C25H32N4O4S2                                                                           517                      541                                                                                 ##STR550##                            C26H34N4O4S2                                                                           531                      542                                                                                 ##STR551##                            C19H22N4O2S2                                                                           517                      543                                                                                 ##STR552##                            C17H21N5O4S2                                                                           424                      544                                                                                 ##STR553##                            C21H31N3O2S2                                                                           422                      545                                                                                 ##STR554##                            C24H26N4O3S2                                                                           483                      546                                                                                 ##STR555##                            C24H29N3O4S2                                                                           488                      547                                                                                 ##STR556##                            C22H25N3O3S2                                                                           444                      548                                                                                 ##STR557##                            C21H25N3O4S2                                                                           448                      549                                                                                 ##STR558##                            C21H25N3O3S2                                                                           432                      550                                                                                 ##STR559##                            C26H30N4O3S2                                                                           511                      551                                                                                 ##STR560##                            C20H23N3O3S2                                                                           418                      552                                                                                 ##STR561##                            C20H23N3O3S2                                                                           418                      553                                                                                 ##STR562##                            C20H23N3O3S2                                                                           418                      554                                                                                 ##STR563##                            C20H22N4O5S2                                                                           463                      555                                                                                 ##STR564##                            C17H25N3O2S2                                                                           368                      556                                                                                 ##STR565##                            C20H23N3O4S2                                                                           434                      557                                                                                 ##STR566##                            C19H22N4O2S2                                                                           517                      558                                                                                 ##STR567##                            C19H22N4O2S2                                                                           517                      559                                                                                 ##STR568##                            C22H24N4O2S2                                                                           441                      560                                                                                 ##STR569##                            C22H28N4O2S2                                                                           559                      561                                                                                 ##STR570##                            C23H26N4O2S2                                                                           569                      562                                                                                 ##STR571##                            C17H21N5O2S3                                                                           538                      563                                                                                 ##STR572##                            C21H25N3O3S2                                                                           432                      564                                                                                 ##STR573##                            C17H21N5O2S2                                                                           506                      565                                                                                 ##STR574##                            C18H21N5O4S2                                                                           436                      566                                                                                 ##STR575##                            C27H36N4O4S2                                                                           545                      567                                                                                 ##STR576##                            C25H32N4O4S2                                                                           517                      568                                                                                 ##STR577##                            C26H34N4O4S2                                                                           531                      569                                                                                 ##STR578##                            C21H22N6O2S3                                                                           487                      570                                                                                 ##STR579##                            C22H28N4O2S2                                                                           559                      571                                                                                 ##STR580##                            C20H24N4O2S2                                                                           531                      572                                                                                 ##STR581##                            C21H26N4O2S2                                                                           545                      573                                                                                 ##STR582##                            C20H24N4O2S2                                                                           531                      574                                                                                 ##STR583##                            C21H26N4O2S2                                                                           545                      575                                                                                 ##STR584##                            C13H15N3O4S2                                                                           342                      576                                                                                 ##STR585##                            C11H13N3O3S2                                                                           300                      577                                                                                 ##STR586##                            C11H14N4O2S2                                                                           413                      578                                                                                 ##STR587##                            C17H23N3O4S2                                                                           398                      579                                                                                 ##STR588##                            C16H21N3O4S2                                                                           384                      580                                                                                 ##STR589##                            C15H21N3O3S2                                                                           356                      581                                                                                 ##STR590##                            C18H18F2N4O3S2                                                                         441                      582                                                                                 ##STR591##                            C18H18F2N4O4S2                                                                         457                      583                                                                                 ##STR592##                            C15H21N3O5S2                                                                           388                      584                                                                                 ##STR593##                            C15H21N3O4S2                                                                           372                      585                                                                                 ##STR594##                            C17H17N3O3S2                                                                           376                      586                                                                                 ##STR595##                            C21H22Cl2N4O2S2                                                                        498                      587                                                                                 ##STR596##                            C21H22F2N4O2S2                                                                         465                      588                                                                                 ##STR597##                            C14H19N3O2S2                                                                           326                      589                                                                                 ##STR598##                            C10H11N3O3S2                                                                           286                      590                                                                                 ##STR599##                            C18H19FN4O4S2                                                                          439                      591                                                                                 ##STR600##                            C18H19FN4O2S2                                                                          407                      592                                                                                 ##STR601##                            C18H19FN4O3S2                                                                          423                      593                                                                                 ##STR602##                            C15H21N3O4S2                                                                           372                      594                                                                                 ##STR603##                            C14H19N3O3S2                                                                           342                      595                                                                                 ##STR604##                            C14H19N3O4S2                                                                           358                      596                                                                                 ##STR605##                            C14H20N4O2S2                                                                           341                      597                                                                                 ##STR606##                            C18H19FN4O2S2                                                                          407                      598                                                                                 ##STR607##                            C18H18F2N4O2S2                                                                         425                      599                                                                                 ##STR608##                            C18H17F3N4O2S2                                                                         443                      600                                                                                 ##STR609##                            C18H19ClN4O2S2                                                                         423                      601                                                                                 ##STR610##                            C21H26N4O2S2                                                                           431                      602                                                                                 ##STR611##                            C15H22N4O3S2                                                                           371                      603                                                                                 ##STR612##                            C16H24N4O3S2                                                                           385                      604                                                                                 ##STR613##                            C19H22N4O3S2                                                                           419                      605                                                                                 ##STR614##                            C19H21FN4O3S2                                                                          437                      606                                                                                 ##STR615##                            C19H22N4O3S2                                                                           419                      607                                                                                 ##STR616##                            C19H20N4O4S2                                                                           433                      608                                                                                 ##STR617##                            C18H27N5O2S2                                                                           524                      609                                                                                 ##STR618##                            C17H22N6O2S2                                                                           521                      610                                                                                 ##STR619##                            C14H17N702S2                                                                           494                      611                                                                                 ##STR620##                            C19H21N5O3S2                                                                           432                      612                                                                                 ##STR621##                            C17H19N5O2S2                                                                           504                      613                                                                                 ##STR622##                            C22H25N5O2S2                                                                           456                      614                                                                                 ##STR623##                            C18H24N6O2S2                                                                           535                      615                                                                                 ##STR624##                            C21H23FN4O2S2                                                                          447                      616                                                                                 ##STR625##                            C21H22F2N4O2S2                                                                         465                      617                                                                                 ##STR626##                            C21H21F3N4O2S2                                                                         483                      618                                                                                 ##STR627##                            C21H23ClN4O2S2                                                                         464                      619                                                                                 ##STR628##                            C24H30N4O2S2                                                                           471                      620                                                                                 ##STR629##                            C18H26N4O3S2                                                                           411                      621                                                                                 ##STR630##                            C19H28N4O3S2                                                                           425                      622                                                                                 ##STR631##                            C22H26N4O3S2                                                                           459                      623                                                                                 ##STR632##                            C22H25FN4O3S2                                                                          477                      624                                                                                 ##STR633##                            C22H26N4O3S2                                                                           459                      625                                                                                 ##STR634##                            C22H24N4O4S2                                                                           473                      626                                                                                 ##STR635##                            C21H31N5O2S2                                                                           564                      627                                                                                 ##STR636##                            C20H26N6O2S2                                                                           561                      628                                                                                 ##STR637##                            C17H21N7O2S2                                                                           534                      629                                                                                 ##STR638##                            C23H29N5O2S2                                                                           586                      630                                                                                 ##STR639##                            C22H25N5O3S2                                                                           472                      631                                                                                 ##STR640##                            C20H23N5O2S2                                                                           544                      632                                                                                 ##STR641##                            C25H29N5O2S2                                                                           496                      633                                                                                 ##STR642##                            C21H28N6O2S2                                                                           575                      634                                                                                 ##STR643##                            C24H33N3O3S2Si                                                                         504                      635                                                                                 ##STR644##                            C23H28N4O4S2                                                                           489                      __________________________________________________________________________     ##STR645##

A solution of 100 mg ofN-[5-[[(5-t-Butyl-2-oxazolyl)methyl]thio]-2-aminothiazole and 68 mg of2,6-difluorophenyl isothiocyanate was heated at 65° C. for 16 hoursunder argon. The solution was evaporated to dryness and the residuepurified by flash chromatography to give 91 mg of the intermediatethiourea.

To a solution of 30 mg ofN-[5-[[(5-t-Butyl-2-oxazolyl)methyl]thio]-2-thiazolyl]-N"-(2,6-difluorophenyl)thiourea,52 mg of ethyl-3(3-dimethylamino)propyl carbodiimide hydrochloride and48 μL of diisopropylethylamine in 0.5 mL methylene chloride was added asolution of 29 mg of cyanamide in 0.1 mL tetrahydrofuran. After stirringfor 1 hr, the solvent was removed and the crude material purified byHPLC to give 8 mg of Example 636 compound.

MS: (M+H)⁺ 449⁺

¹ H NMR (400 MHz, CDCl₃): d 1.27 (9 H, s), 4.19 (2 H, s), 6.69 (1 H, s),7.03 (2 H, m), 7.35 (1 H, m), 8.74 (1 H, s). ##STR646##

To a stirred mixture of 2-acetamido-5-thiazole thiol acetate (141 mg) in3 mL of dry THF under argon was added 1 N t-BuOK in THF (0.72 mL). Thismixture was stirred at room temperature for 25 min, and a solution of5-isopropyl-(2-(chlorofluoromethyl))oxazole (116 mg) in 2 mL of dry THFwas added. The reaction mixture was stirred at 60° C. for 18 hr, dilutedwith 150 mL of EtOAc and washed with saturated NH₄ Cl solution (2×25mL), saturated NaHCO₃ solution (1×25 mL) and brine (1×25 mL). Theorganic layer was dried (MgSO₄), filtered and concentrated in vacuo togive Example 637 compound.

MS: (M+H)+316 HPLC retention time 3.52 min. (Column: YMC ODS S05 4.6×50mm column, 0% to 100% B gradient in 4 min. Solvent A: 10% CH₃ OH/90% H₂O/0.2% H₃ PO₄ ; Solvent B: 90% CH₃ OH/10% H₂ O/0.2% H₃ PO₄ ; UV: 220nM).

What is claimed is:
 1. A compound of the formula ##STR647## andpharmaceutically acceptable salts thereof wherein: R₁ and R₂ areindependently hydrogen, fluorine or alkyl;R₃ is aryl or heteroaryl; R₄is alkyl, cycloalkyl, aryl, cycloalkylalkyl, arylalkyl, heteroaryl,heteroarylalkyl, heterocycloalkyl,heterocycloalkylalkyl; or CO-alkyl,CO-cycloalkyl, CO-aryl, CO-alkyl-cycloalkyl,CO-alkyl-aryl,CO-heteroaryl, CO-alkyl-heteroaryl, CO-heterocycloalkyl,CO-alkyl-heterocycloalkyl; or CONH-alkyl, CONH-cycloalkyl, CONH-aryl,CONH-alkyl-cycloalkyl, CONH-alkyl-aryl,CONH-heteroaryl,CONH-alkyl-heteroaryl, CONH-heterocycloalkyl,CONH-alkyl-heterocycloalkyl; or COO-alkyl, COO-cycloalkyl, COO-aryl,COO-alkyl-cycloalkyl,COO-alkyl-aryl, COO-heteroaryl,COO-alkyl-heteroaryl, COO heterocycloalkyl, COO-alkyl-heterocycloalkyl;or SO₂ -cycloalkyl, SO₂ -aryl, SO₂ -alkyl-cycloalkyl, SO₂ -alkyl-aryl,SO₂ -heteroaryl, SO₂ -alkyl-heteroaryl, SO₂ -heterocycloalkyl, SO₂-alkyl-heterocycloalkyl; or C(NCN)NH-alkyl, C(NCN)NH-cycloalkyl,C(NCN)NH-aryl,C(NCNNH)-alkyl-cycloalkyl, C(NCN)NH-alkyl-aryl,C(NCN)NH-heteroaryl, C(NCN)NH-alkyl-heteroaryl,C(NCN)NH-heterocycloalkyl, C(NCN)NH-alkyl-heterocylcoalkyl; orC(NNO₂)NH-alkyl, C(NNO₂)NH-cycloalkyl,C(NNO₂)NH-aryl,C(NNO₂)NH-alkyl-cycloalkyl, C(NNO₂)NH-alkyl-aryl,C(NNO₂)NH-heteroaryl, C(NNO₂)NH-alkyl-heteroaryl,C(NNO₂)NH-heterocyloalkyl, C(NNO₂)NH-alkyl-heterocycloalkyl; orC(NH)NH-alkyl, C(NH)NH-cycloalkyl,C(NH)NH-aryl,C(NH)NH-alkyl-cycloalkyl, C(NH)NH-alkyl-aryl,C(NH)NH-heteroaryl, C(NH)NH-alkyl-heteroaryl, C(NH)NH-heterocycloalkyl,C(NH)NH-alkyl-heterocycloalkyl; or C(NH)NHCO-alkyl,C(NH)NHCO-cycloalkyl, C(NH)NHCO-aryl,C(NH)NHCO-alkyl-cycloalkyl,C(NH)NHCO-alkyl-aryl, C(NH)NHCO-heteroaryl, C(NH)NHCO-alkyl-heteroaryl,C(NH)NHCO-heterocylcloalkyl, C(NH)NHCO-alkyl-heterocycloalkyl; orC(NOR₆)NH-alkyl, C(NOR₆)NH-cycloalkyl,C(NOR₆)NH-aryl,C(NOR₆)NH-alkyl-cycloalkyl, C(NOR₆)NH-alkyl-aryl,C(NOR₆)NH-heteroaryl, C(NOR₆)NH-alkyl-heteroaryl,C(NOR₆)NH-heterocylcoalkyl, C(NOR₆)NH-alkyl-heterocycloalkyl; R₅ ishydrogen or alkyl; R₆ is hydrogen, alkyl, cycloalkyl, aryl,cycloalkylakyl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkylor heterocycloalkylalkyl; m is an integer of 0 to 2; and n is an integerof 1 to
 3. 2. The compounds as recited in claim 1, whereinR₁ and R₂ areindependently hydrogen, fluorine or alkyl; ##STR648## wherein Y isoxygen, sulfur or NR₉ R₃ is alkyl, cycloalkyl, aryl, cyoloalkylalkyl,arylalkyl, heteroaryl, heteroarylalkyl,heterocycloalkyl,heterocycloalkylalkyl, or CO-alkyl, CO-cycloalkyl,CO-aryl, CO-alkyl-cycloalkyl, CO-alkyl-aryl,CO-heteroaryl,CO-alkyl-heteroaryl, CO-heterocycloalkyl, CO-alkyl-heterocycloalkyl; orCONH-alkyl, CONH-cycloalkyl, CONH-aryl, CONH-alkyl-cycloalkyl,CONH-alkyl-aryl, CONH-heteroaryl,CONH-alkyl-heteroaryl,CONH-heterocycloalkyl, CONH-alkyl-heterocycloalkyl; or COO-alkyl,COO-cycloalkyl, COO-aryl, COO-alkyl-cycloalkyl,COO-alkyl-aryl,COO-heteroaryl, COO-alkyl-heteroaryl, COO-heterocycloalkyl,COO-alkyl-heterocycloalkyl; or SO₂ -cycloalkyl, SO₂ -aryl, SO₂-alkyl-cycloalkyl, SO₂ -alkyl-aryl,SO₂ -heteroaryl, SO₂-alkyl-heteroaryl, SO₂ -heterocycloalkyl, SO₂ -alkyl-heterocycloalkyl;or C(NCN)NH-alkyl, C(NCN)NH-cycloalkyl,C(NCN)NH-aryl,C(NCNNH)-alkyl-cycloalkyl, C(NCN)NH-alkyl-aryl,C(NCN)NH-heteroaryl, C(NCN)NH-alkyl-heteroaryl, C(NCN)NH-heterocycloalkyl, C(NCN)NH-alkyl-heterocylcoalkyl; or C(NNO₂)NH-alkyl,C(NNO₂)NH-cycloalkyl, C(NNO₂)NH-aryl,C(NNO₂)NH-alkyl-cycloalkyl,C(NNO₂)NH-alkyl-aryl, C(NNO₂)NH-heteroaryl, C(NNO₂)NH-alkyl-heteroaryl,C(NNO₂)NH-heterocyloalkyl, C(NNO₂) NH-alkyl-heterocycloalkyl; orC(NH)NH-alkyl, C(NH)NH-cycloalkyl,C(NH)NH-aryl,C(NH)NH-alkyl-cycloalkyl, C(NH)NH-alkyl-aryl,C(NH)NH-heteroaryl, C(NH)NH-alkyl-heteroaryl, C(NH)NH-heterocycloalkyl,C(NH)NH-alkyl-heterocycloalkyl; or C(NH)NHCO-alkyl,C(NH)NHCO-cycloalkyl, C(NH)NHCO-aryi,C(NH)NHCO-alkyl-cycloalkyl, C(NH)NHC alkyl-aryl, C(NH)NHCO-heteroaryl, C(NH)NHCO-alkyl-heteroaryl,C(NH)NHCO-heterocylcloalkyl, C(NH)NHCO-alkyl-heterocycloalkyl; orC(NOR₆)NH-alkyl, C(NOR₆)NH-cycloalkyl,C(NOR₆)NH-aryl,C(NOR₆)NH-alkyl-cycloalkyl, C(NOR₆)NH-alkyl-aryl,C(NOR₆)NH-heteroaryl, C(NOR₆)NH-alkyl-heteroaryl,C(NOR₆)NH-heterocylcoalkyl, C(NOR₆)NH-alkyl-heterocycloalkyl; R₅ ishydrogen or alkyl: R₆ is hydrogen, alkyl, cycloalkyl, aryl,cycloalkylakyl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkylor heterocycloalkylalkyl; R₇ and R₈ are independently hydrogern, alkyl,substituted alkyl, cycloalkyl, aryl, substituted aryl, cycloalkylalkyl,arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl,heterocycloalkyl, heterocycloalkyalkyl; R₈ is hydrogen, alkyl,cycloalkyl, aryl, akylcycloalkyl, arylalkyl, heteroaryl,heteroarylalkyl, heterocycloalkyl or heterocycloalkylalkyl; m is aninteger of 0 to 2; and n is an inteaer of 1 to
 3. 3. The compounds asrecited in claim 1, whereinR₁ and R₂ are independently hydrogen,fluorine or alkyl; ##STR649## wherein Y is oxygen; R₄ is alkyl,cycloalkyl, aryl, cycloalkylalkyl, arylalkyl, heteroaryl,heteroarylalkyl, heterocycloalkyl,heterocycloalkylalkyl; or CO-alkyl,CO-cycloalkyl, CO-aryl, CO-alkyl-cycloalkyl,CO-alkyl-aryl,CO-heteroaryl, CO-alkyl-heteroaryl, CO-heterocycloalkyl,CO-alkyl-heterocycloalkyl; or CONH-alkyl, CONH-cycloalkyl, CONH-aryl,CONH-alkyl-cycloalkyl, CONH-alkyl-aryl,CONH-heteroaryl,CONH-alkyl-heteroaryl, CONH-heterocycloalkyl,CONH-alkyl-heterocycloalkyl; or COO-alkyl, COO-cycloalkyl, COO-aryl,COO-alkyl-cycloalkyl,COO-alkyl-aryl, CO-heteroaryl,COO-alkyl-heteroaryl, COO-heterocycloalkyl, COO-alkyl-heterocycloalkyl;or SO₂ -cycloalkyl, SO₃ -aryl, SO₂ -alkyl-cycloalkyl, SO₂-alkyl-aryl,SO₂ -heteroaryl, SO₂ -alkyl-heteroaryl, SO₂-heterocycloalkyl, SO₂ -alkyl-heterocycloalkyl; or C(NCN)NH-alkyl,C(NCN)NH-cycloalkyl, C(NCN)NH-aryl,C(NCNNH)-alkyl-cycloalkyl,C(NCN)NH-alkyl-aryl, C(NCN)NH-heteroaryl, C(NCN)NH-alkyl-heteroaryl,C(NCN)NH-heterocycloalkyl, C(NCN)NH-akyl-heterocylcoalkyl; orC(NNO₂)NH-alkyl, C(NNO₂)NH-cycloalkyl,C(NNO₂)NH-aryl,C(NNO₂)NH-alkyl-cycloalkyl, C(NNO₂)NH-alkyl-aryl,C(NNO₂)NH-heteroaryl, C(NNO₂)NH-alkyl-heteroaryl,C(NNO₂)NH-heterocyloalkyl, C(NNO₂)NH-alkyl-heterocycloalkyl; orC(NH)NH-alkyl, C(NH)NH-cycloalkyl,C(NH)NH-ayrl,C(NH)NH-alkyl-cycloalkyl, C(NH)NH-alkyl-aryl,C(NH)NH-heteroaryl, C(NR)NH-alkyl-heteroaryl, C(NH)NH-heterocycloalkyl,C(NH)NH-alkyl-heterocycloalkyl; or C(NH)NHCO-alkyl,C(NH)NHCO-cycloalkyl, C(NNOH)NHCO-aryl,C(NH)NHCO-alkyl-cycloalkyl,C(NH)NHCO alkyl-aryl; C(NH)NHCO-heteroaryl, C(NH)NHCO-alkyl-heteroaryl,C(NH)NHCO-heterocylcloalkyl, C(NH)NHCO-alkyl-heterocycloalkyl; orC(NOR₆)NH-alkyl, C(NOR₂)NH-cycloalkyl,C(NOR₆)NH-aryl,C(NOR₅)NH-alkyl-cycloalkyl, C(NOR₅)NH-alkyl-aryl,C(NOR₅)NH-heteroaryl, C(NOR₅)NH-alkyl-heteroaryl,C(NOR₆)NH-heterocylcoalkyl, C(NOR₅)NH-alkyl-heterocycloalkyl; R₅ ishydrogen; R₅ is hydrogen, alkyl, cycloalkyl, aryl, cyclolkylakyl,arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl orheterocycloalkylalkyl; R₇ and R₅ are independently hydrogen, alkyl,substituted alkyl, cycloalkyl, aryl, subsituted aryl, cycloal kylalkyl,arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl,heterocycloalkyl, heterocycloalkyalkyl; m is an integer of 0 to 2; and nis an integer of 1 to
 3. 4. The compounds as recited in claim 1,whereinR₁ and R₂ are independently hydrogen, fluorine or alkyl;##STR650## wherein Y is sulfur; R₆ is alkyl, cycloalkyl, aryl,oycloalkylalkyl, arylalkyl, heteroaryl, heteroarylalkyl,heterocycloalkyl,heterocycloalkylalkyl, or CO-alkyl, CO-cycloalkyl,CO-aryl, CO-alkyl-cycloalkyl, CO-alkyl-aryl,CO-heteroaryl,CO-alkyl-heteroaryl, CO-heterocycloalkyl, CO-alkyl-heterocycloalkyl; orCONH-alkyl, CONH-cycloalkyl, CONH-aryl, CONH-alkyl-cycloalkyl,CONH-alkyl-aryl, CONH-heteroaryl,CONH-alkyl-heteroaryl,CONH-heterocycloalkyl, CONH-alkyl-heterocycloalkyl: or COO-alkyl,COO-cycloalkyl, COO-aryl, COO-alkyl-cycloalkyl,COO-alkyl-aryl,COO-heteroaryl, COO-alkyl-heteroaryl, COO-heterocycloalkyl,COO-alkyl-heterocycloalkyl; or SO₂ -cycloalkyl, SO₂ -aryl, SO₂-alkyl-cyloalkyl, SO₂ -alkyl-aryl,SO₂ -heteroaryl, SO₂-alkyl-heteroaryl, SO₂ -heterocycloalkyl, SO₂ -alkyl-heterocycloalkyl;or C(NCN)NH-alkyl, C(NCN)NH-cycloalkyl,C(NCN)OH-aryl,C(NCNNH)-alkyl-cycloalkyl, C(NCN)NH-alkyl-aryl,C(NCN)NH-heteroaryl, C(NCN)NH-alkyl-heteroaryl,C(NCN)NH-heterocycloalkyl, C(NCN)NH-alkyl-heterocylcoalkyl; orC(NNO₂)NH-alkyl, C(NNO₂)NH-cycloalkyl,C(NNO₂)NH-aryl,C(NNO₂)NH-alkyl-cycloalkyl, C(NNO₂)NH-alkyl-aryl,C(NNO₂)NH-heteroaryl, C(NNO₂)NH-alkyl-heteroaryl,C(NNO₂)NH-heterocyloalkyl, C(NNO)NH-alkyl-heterocycloalkyl; orC(NH)NH-alkyl, C(NH)NH-cycloalkyl,C(NH)NH-aryl,C(NH)NH-alkyl-cycloalkyl, C(NH)NH-alkyl-aryl,C(NH)NH-heteroaryl, C(NH)NH-alkyl-heteroaryl, C(NH)NH-heterocycloalkyl,C(NH)NH-alkyl-heterocycloalkyl; or C(NH)NHCO-alkyl,C(NH)NHCO-cycloalkyl, C(NH)NHCO-aryl,C(NH)NHCO-alkyl-cycloalkyl,C(NH)NHCO-alkyl-aryl, C(NH)NHCO-heteroaryl, C(NH)NHCO-alkyl-heteroaryl,C(NH)NHCO-heterocylcloalkyl, C(NH)NHCO-alkyl-heterocycloalkyl; orC(NOR₆)NH-alkyl, C(NOR₆)NH-cycloalkyl,C(NOR₆)NH-aryl,C(NOR₆)NH-alkylcycloalkyl, C(NOR₆)NH-alkyl-aryl,C(NOR₆)NH-heteroaryl, C(NOR₆)NH-alkyl-heteroaryl,C(NOR₆)NH-heterocylcoalkyl, C(NOR₆)NH-alkyl-heterocycloalkyl; R₆ ishydrogen; R₆ is hydrogen, alkyl, cycloalkyl, aryl, cycloalkylakyl,arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl orheterocycloalkylalkyl; R₇ and R₈ are independently hydrogen, alkyl,substituted alkyl, cycloalkyl, aryl, substituted aryl, cycloalkylalkyl,arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl,heterocycloalkyl, heterocycloalkyalkyl; m is an integer of 0 to 2; and nis an integer of 1 to
 3. 5. The compounds as recited in claim 1,whereinR₁ and R₂ are independently hydrogen, fluorine or alkyl;##STR651## wherein Y is NR₉ ; R₄ is alkyl, cycloalkyl, aryl,cycloalkylalkyl, arylalkyl, heteroaryl, heteroarylalkyl,heterocycloalkyl,heterocycloalkylalkyl; or CO-alkyl, CO-cycloalkyl,CO-aryl, CO-alkyl-cycloalkyl, CO-alkyl-aryl,CO-heteroaryl,CO-alkyl-heteroaryl, CO-heterocycloalkyl, CO-alkyl-heterocycloalkyl; orCONH-alkyl, CONH-cycloalkyl, CONH-aryl, CONH-alkyl-cycloalkyl,CONH-alkyl-aryl, CONH-heteroaryl,CONH-alkyl-heteroaryl,CONH-heterocycloalkyl, CONH-alkyl-heterocycloalkyl; or COO-alkyl,COO-cycloalkyl, COO-aryl, COO-alkyl-cycloalkyl,COO-alkyl-aryl,COO-heteroaryl, COO-alkyl-heteroaryl, COO-heterocycloalkyl,COO-alkyl-heterocycloalkyl; or SO₂ -cycloalkyl, SO₂ -aryl, SO₂-alkyl-cycloalkyl, SO₂ -alkyl-aryl, SO₂ -heteroaryl, SO₂-alkyl-heteroaryl, SO₂ -heterocycloalkyl, SO₂ -alkyl-heterocycloalkyl;or C(NCN)NH-alkyl, C(NCN)NH-cycloalkyl, C(NCN)NH-aryl,C(NCNNH)-alkyl-cycloalkyl, C(NCN)NH-alkyl-aryl, C(NCN)NH-heteroaryl,C(NCN)NH-alkyl-heteroaryl, C(NCN)NH-heterocycloalkyl,C(NCN)NH-alkyl-heterocylcoalkyl; or C(NNO₂)NH-alkyl,C(NNO₂)NH-cycloalkyl, C(NNO₂)NH-aryl,C(NNO₂)NH-alkyl-cycloalkyl,C(NNO₃)NH-alkyl-aryl, C(NNO₂)NH-heteroaryl, C(NNO₂)NH-alkylheteroaryl,C(NNO₂)NH-heterocyloalkyl, C(NNO₂)NH-alkyl-heterocycloalkyl; orC(NH)NH-alkyl, C(NH)NH-cycloalkyl,C(NH)NH-aryl,C(NH)NH-alkyl-cycloalkyl, C(NH)NH-alkyl-aryl,C(NH)NH-heteroaryl, C(NH)NH-alkyl-heteroaryl, C(NH)NH-heterocycloalkyl,C(NH)NH-alkyl-heterocycloakyl; or C(NH)NHCO-alkyl, C(NH)NHCO-cycloalkyl,C(NH)NHCO-aryl,C(NH)NHCO-alkyl-cycloalkyl, C(NH)NHCO-alkyl-aryl,C(NH)NHCO-heteroaryl, C(NH)NHCO-alkyl-heteroaryl,C(NH)NHCO-heterocylcloalkyl, C(NH)NHCO-alkyl-heterocycloalkyl; orC(NOR₈)NH-alkyl, C(NOR₆)NH-cycloalkyl,C(NOR₆)NH-aryl,C(NOR₆)NH-alkyl-cycloalkyl, C(NOR₅)NH-alkyl-aryl,C(NOR₆)NH-heteroaryl, C(NOR₆)NH-alkyl-heteroaryl,C(NOR₆)NH-heterocylcoalkyl, C(NOR₆)NH-alkyl-heterocycloalkyl; R₅ ishydrogen, R₅ is hydrogen, alkyl, cycloalkyl, aryl, cycloalkylakyl,arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl orheterocycloalkylalkyl; R₇ and R₈ are independently hydrogen, alkyl,substituted alkyl, cycloalkyl, aryl, subsituted aryl, cycloalkylalkyl,arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl,heterocycloalkyl, heterocycloalkylalkyl; R₉ is hydrogen, alkylcycloalkyl, aryl, cycloalkylakyl, arylalkyl, heteroaryl,heteroarylalkyl, heterocycloalkyl or heterocycloalkylalkyl; m is aninteger of 0 to 2; and n is an integer of 1 to
 3. 6. The compounds asrecited in claim 1, whereinR₁ and R₂ are independently hydrogen,fluorine or alkyl; ##STR652## wherein Y is oxygen; R₄ is CO-alkyl,CO-alkyl-aryl, CO-cycloalkyl, CO-alkyl-heteroaryl, CO-alkyl-heteroalkyl,CO-alkyl-heterocycloalkyl, CONH-alkyl, CONH-alkyl-aryl, CONH-cycloalkyl,or CONH-alkyl-heterocycloalkyl; R₅ is hydrogen; and R₇ and R₈ arehydrogen; m is the integer 0; and n is the integer
 1. 7. The compoundsas recited in claim 1, whereinR₁ and R₂ are independently hydrogen,fluorine or alkyl; ##STR653## wherein Y is oxygen; R₄ is CO-alkyl,CO-alkyl-aryl, CO-alkyl-heteroalkyl, CO-cycloalkyl,CO-alkyl-heterocycloalkyl, CO-alkyl-heteroaryl, CONH-alkyl,CONH-alkyl-aryl, CONH-cycloalkyl, or CONH-alkyl-heterocycloalkyl; R₅ ishydrogen; R₇ and R₈ are alkyl; m is the integer 0; and n is theinteger
 1. 8. The compounds as recited in claim 1, whereinR₁ and R₂ areindependently hydrogen, fluorine or alkyl; ##STR654## wherein Y isoxygen; R₄ is CO-alkyl, CO-alkyl-aryl, CO-alkyl-heteroalkyl,CO-cycloalkyl, CO-alkyl-heterocycloalkyl, CO-alkyl-heteroaryl,CONH-alkyl, CONH-alkyl-aryl, CONH-cycloalkyl, orCONH-alkyl-heterocycloalkyl; R₅ is hydrogen; R₇ is hydrogen; R₈ isalkyl; m is the integer 0; and n is the integer
 1. 9. The compounds asrecited in claim 1, whereinR₁ and R₂ are independently hydrogen,fluorine or alkyl; ##STR655## wherein Y is oxygen; R₄ is CO-alkyl,CO-alkyl-aryl, CO-alkyl-heteroalkyl, CO-cycloalkyl,CO-alkyl-heterocycloalkyl, CO-alkyl-heteroaryl, CONH-alkyl,CONH-alkyl-aryl, CONH-cycloalkyl, or CONH-alkyl-heterocycloalkyl; R₅ ishydrogen; R₇ is alkyl; R₈ is hydrogen; m is the integer 0; and n is theinteger
 1. 10. The compounds as recited in claim 1, whereinR₁ and R₂ areindependently hydrogen, fluorine or alkyl; ##STR656## wherein Y issulfur; R₄ is CO-alkyl, CO-alkyl-aryl, CO-alkyl-heteroalkyl,CO-cycloalkyl, CO-alkyl-heterocycloalkyl, CO-alkyl-heteroaryl,CONH-alkyl, CONH-alkyl-aryl, CONH-cycloalkyl, orCONH-alkyl-heterocycloalkyl; R₅ is hydrogen; R₇ is hydrogen; R₈ isalkyl; m is the integer 0; and n is the integer
 1. 11. The compounds asrecited in claim 1, whereinR₁ and R₂ are independently hydrogen,fluorine or alkyl; ##STR657## wherein Y is sulfur; R₄ is CO-alkyl,CO-alkyl-aryl, CO-alkyl-heteroalkyl, CO-cycloalkyl,CO-alkyl-heterocycloalkyl, CO-alkyl-heteroaryl, CONH-alkyl,CONH-alkyl-aryl, CONH-cycloalkyl, or CONH-alkyl-heterocycloalkyl; R₅ ishydrogen; R₇ is alkyl; R₈ is hydrogen; m is the integer 0; and n is theinteger
 1. 12. The compounds as recited in claim 1, whereinR₁ and R₂ areindependently hydrogen, fluorine or alkyl; ##STR658## wherein Y is NR₉ ;R₄ is CO-alkyl, CO-alkyl-aryl, CO-alkyl-heteroalkyl, CO-cycloalkyl,CO-alkyl-heterocycloalkyl, CO-alkyl-heteroaryl, CONH-alkyl,CONH-alkyl-aryl, CONH-cycloalkyl, or CONH-alkyl-heterocycloalkyl; R₅ ishydrogen; R₇ is hydrogen; R₈ is alkyl; R₉ is hydrogen, alkyl,cycloalkyl, aryl, alkyl-cycloalkyl, alkyl-aryl, heteroaryl,alkyl-heteroaryl, heterocycloalkyl, or alkyl-heterocycloalkyl; m is theinteger 0; and n is the integer
 1. 13. The compounds as recited in claim1, whereinR₁ and R₂ are independently hydrogen, fluorine or alkyl;##STR659## wherein Y is NR₉ ; R₄ is CO-alkyl, CO-alkyl-aryl,CO-alkyl-heteroalkyl, CO-cycloalkyl, CO-alkyl-heterocycloalkyl,CO-alkyl-heteroaryl, CONH-alkyl, CONH-alkyl-aryl, CONH-cycloalkyl, orCONH-alkyl-heterocycloalkyl; R₅ is hydrogen; R₇ is alkyl; R₈ ishydrogen; R₉ is alkyl; m is the integer 0; and n is the integer
 1. 14.The compounds as recited in claim 1, whereinR₁ and R₂ are independentlyhydrogen, fluorine or alkyl; ##STR660## wherein X is NR₉ ; R₄ isCO-alkyl, CO-alkyl-aryl, CO-cycloalkyl, CO-alkyl-heteroaryl,CO-alkyl-heteroalkyl, CO-alkyl-heterocycloalkyl, CONH-alkyl,CONH-alkyl-aryl, CONH-cycloalkyl, or CONH-alkyl-heterocycloalkyl; R₅ ishydrogen; R₇ is alkyl; R₈ is hydrogen; R₉ is hydrogen; m is the integer0 n is the integer
 1. 15. The compound as recited in claim 1, whichisN-[5-[[5-Ethyl-2-oxazolyl)methyl]thio]-2-thiazoly]acetamide;N-[5-[[5-Ethyl-2-oxazolyl)methyl]thio]-2-thiazolyl]benzamide;N-[5-[[5-Ethyl-2-oxazolyl)methyl]thio]-2-thiazolyl]benzenesulfonamide;N-[5-[[(4,5-Dimethyl-2-oxazolyl)methyl]thio]-2-thiazolyl]acetamide;N-[5-[[(5-t-Butyl-2-oxazolyl)methyl]thio]-2-thiazolyl]acetamide;N-[5-[[5-t-Butyl-2-oxazolyl)methyl]thio]-2-thiazolyl]trimethylacetamide;N-[5-[[(4-Ethyl-2-oxazolyl)methyl]thio]-2-thiazolyl]acetamide; or apharmaceutically acceptable salt thereof.
 16. A pharmaceuticalcomposition comprising a compound of claim 1 and a pharmaceuticallyacceptable carrier.
 17. A pharmaceutical composition comprising acompound of claim 1, in combination with a pharmaceutically acceptablecarrier, and an anti-cancer agent formulated as a fixed dose.
 18. Apharmaceutical composition according to claim 16, comprising a compoundof claim 1 in combination with a pharmaceutically acceptable carrier,with an anticancer treatment or anticancer agent administered insequence.
 19. The pharmaceutical composition according to claim 18,wherein said combination comprising said compound of claim 1 and saidpharmaceutically acceptable carrier, is administered prior toadministration of said anticancer treatment or anticancer agent.
 20. Thepharmaceutical composition according to claim 18, wherein saidcombination comprising said compound of claim 1 and saidpharmaceutically acceptable carrier, is administered afteradministration of said anticancer treatment or anticancer agent.
 21. Amethod of inhibiting protein kinases which comprises administering to amammalian specie in need thereof an effective protein kinase inhibitingamount of a compound of claim
 1. 22. A method of inhibiting cyclindependent kinases which comprises administering to a mammalian specie inneed thereof an effective cyclin dependent kinase inhibiting amount of acompound of claim
 1. 23. A method of inhibiting cdc2 (cdk1) whichcomprises administering to a mammalian specie in need thereof aneffective cdc2 inhibiting amount of a compound of claim
 1. 24. A methodof inhibiting cdk2 which comprises administering to a mammalian speciein need thereof an effective cdk2 inhibiting amount of a compound ofclaim
 1. 25. A method of inhibiting cdk3 which comprises administeringto a mammalian specie in need thereof an effective cdk3 inhibitingamount of a compound of claim
 1. 26. A method of inhibiting cdk4 whichcomprises administering to a mammalian specie in need thereof aneffective cdk4 inhibiting amount of a compound of claim
 1. 27. A methodof inhibiting cdk5 which comprises administering to a mammalian speciein need thereof an effective cdk5 inhibiting amount of a compound ofclaim
 1. 28. A method of inhibiting cdk6 which comprises administeringto a mammalian specie in need thereof an effective cdk6 inhibitingamount of a compound of claim
 1. 29. A method of inhibiting cdk7 whichcomprises administering to a mammalian specie in need thereof aneffective cdk7 inhibiting amount of a compound of claim
 1. 30. A methodof inhibiting cdk8 which comprises administering to a mammalian speciein need thereof an effective cdk8 inhibiting amount of a compound ofclaim
 1. 31. A method for treating proliferative diseases comprisin gadministering to a mammalian specie in need thereof a therapeuticallyeffective amount of a composition of claim
 16. 32. A method for treatingcancer comprising administering to a mammalian specie in need thereof atherapeutically effective amount of a composition of claim
 16. 33. Amethod for treating inflammation, inflamatory bowel disease, ortransplantation rejection, comprising administering to a mammalianspecie in need thereof a therapeutically effective amount of acomposition of claim
 16. 34. A method for treating arthritis comprisingadministering to a mammalian specie in need thereof a therapeuticallyeffective amount of a composition of claim
 16. 35. A method for treatinginfection by HIV, or for treating and preventing the development ofAIDS, comprising administering to a mammalian specie in need thereof atherapeutically effective amount of a composition of claim
 16. 36. Amethod for treating viral infections, comprising administering to amammalian specie in need thereof a therapeutically effective amount of acomposition of claim
 16. 37. A method for treating fungal infections,comprising administering to a mammalian specie in need thereof atherapeutically effective amount of a composition of claim
 16. 38. Amethod for preventing the development of cancer or tumor relapse,comprising administering to a mammalian specie in need thereof atherapeutically effective amount of a composition of claim
 16. 39. Amethod for treating neurodegenerative disease, comprising administeringto a mammalian specie in need thereof a therapeutically effective amountof a composition of claim
 16. 40. A method for treating proliferativediseases comprising administering to a mammalian specie in need thereofa therapeutically effective amount of a composition of claim
 17. 41. Amethod for treating cancer comprising administering to a mammalianspecie in need thereof a therapeutically effective amount of acomposition of claim
 17. 42. A method for preventing the development ofcancer or tumor relapse, comprising administering to a mammalian speciein need thereof a therapeutically effective amount of a composition ofclaim
 17. 43. A method for treating proliferative diseases comprisingadministering to a mammalian specie in need thereof a therapeuticallyeffective amount of a composition of claim
 18. 44. A method for treatingcancer comprising administering to a mammalian specie in need thereof atherapeutically effective amount of a composition of claim
 18. 45. Amethod for preventing the development of cancer or tumor relapse,comprising administering to a mammalian specie in need thereof atherapeutically effective amount of a composition of claim 18.